DPP1 inhibitors having polycyclic linkers and their use

Abstract

Compounds of formula (I), or pharmaceutically acceptable salts or deuterated forms thereof, are provided herein, where R 0 , L, and R 1 This is defined herein. Also provided herein are pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt or deuterated form thereof, and methods of using a compound of formula (I), or a pharmaceutically acceptable salt or deuterated form thereof, for example, to treat a disease treatable by the administration of a DPP1 inhibitor. JPEG2026510867000785.jpg3240

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 452,636 filed on 16 March 2023 and U.S. Provisional Application No. 63 / 546,686 filed on 31 October 2023, the entire contents of which are incorporated herein by reference for all purposes. [Background technology]

[0002] Dipeptidyl peptidase 1 (DPP1, EC 3.4.14.1), also known as cathepsin C, is a lysosomal cysteine ​​protease belonging to the papain family with a molecular weight of 200 kDa. DPP1 was first discovered in 1948 by Gutman and Fruton (J Biol Chem, 174, 851-858), but the cDNA of the human enzyme was first described in 1995 (Paris et al. 1995, FEBS Lett, 369, 326-330). DPP1 is the only member of the papain family that functions as a tetramer, consisting of four identical subunits. Each subunit consists of an N-terminal fragment, a heavy chain, and a light chain (Dolenc et al. 1995, J Biol Chem, 270, 21626-21631).

[0003] DPP1 is constitutively expressed in many tissues, with the highest levels in the lungs, kidneys, liver, and spleen. DPP1 catalyzes the removal of dipeptides from the N-terminus of polypeptide substrates with broad specificity. Recent data suggest that, in addition to being a key enzyme in lysosomal proteolysis, DPP1 also functions as a key enzyme in the activation of granular serine proteases in cytotoxic T lymphocytes and natural killer cells (granzymes A and B), mast cells (chymase and tryptase), and neutrophils (cathepsin G, neutrophil elastase, and proteinase-3).

[0004] Mast cells are found in many tissues, but are more numerous along the inner lining of epithelium in the body, such as in the skin, respiratory tract, and digestive tract. In humans, two types of mast cells have been identified: type T, which expresses only tryptase, and type MC, which expresses both tryptase and chymase. In humans, type T mast cells are mainly found in alveolar tissue and intestinal mucosa, while type TC cells are more abundant in the skin and conjunctiva. Tryptase and chymase are thought to be important mediators in allergic diseases, involved in the processes of inflammation, bronchoconstriction, and mucus secretion.

[0005] Neutrophils play a crucial role in host defense against invading pathogens. Produced in the bone marrow and released into circulation, neutrophils fully mature and assume their role as the first line of defense. Pro-inflammatory mediators and chemotactic attractants activate neutrophils, drawing them to the site of infection, where they phagocytose bacteria and attack them with a stockpile of antimicrobial compounds using both oxidative and non-oxidative attack methods. Neutrophil elastase, a potent serine protease, is one antimicrobial compound clearly involved in bacterial destruction. Neutrophil elastase is released into the phagolithosome surrounding the microorganism, which leads to its destruction. Neutrophil elastase can attack OmpA, an outer membrane protein in Gram-negative bacteria, not only directly killing the pathogen by degrading its membrane but also allowing other antimicrobial compounds to access the pathogen. Furthermore, neutrophil elastase can help process other antimicrobial compounds, such as cathelicidin, converting them from inactive propeptides to their active state.

[0006] However, neutrophil elastase can also cause problems for its host. It is one of the most destructive enzymes in the body and has the ability to degrade extracellular matrix proteins (including collagen, proteoglycans, fibronectin, platelet receptors, complement receptors, thrombomodulin, pulmonary surfactants, and cadherins) as well as major plasma proteins (including coagulation factors and complement factors, immunoglobulins, and several proteases and protease inhibitors). Under physiological conditions, endogenous protease inhibitors such as α1-antitrypsin tightly regulate neutrophil elastase activity. However, at inflammatory sites, neutrophil elastase can evade regulation, and when unregulated, it can induce the release of pro-inflammatory cytokines such as interleukin-6 and interleukin-8, potentially leading to acute lung injury. It can even impair host defense against infection by degrading phagocytic cell surface receptors and opsonins. Its negative role is demonstrated by its involvement in tissue destruction and inflammation that characterize many diseases, including hereditary emphysema, chronic obstructive pulmonary disease, cystic fibrosis, adult respiratory distress syndrome, ischemia-reperfusion injury, and rheumatoid arthritis. Therefore, there is a need in the art to provide novel DPP1 inhibitors for the treatment of the aforementioned diseases, as well as other diseases related to DPP1 and neutrophil elastase. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Paris et al.1995,FEBS Lett,369,326-330 [Non-Patent Document 2] Dolenc et al.1995,J Biol Chem,270,21626-21631 [Overview of the Initiative] [Means for solving the problem]

[0008] In some embodiments, the present disclosure provides a compound of formula (I), [Chemical formula] or a pharmaceutically acceptable salt or deuterated form thereof, wherein, R 10 is ● a 5- to 12-membered monocyclic heterocyclyl containing 1 to 3 heteroatoms selected from N, S, O, wherein the monocyclic heterocycle is optionally substituted with 1 to 3 R 8 , a 5- to 12-membered monocyclic heterocyclyl, or ● a 5- to 12-membered polycyclic heterocyclyl containing 1 to 3 heteroatoms selected from N, S, O, wherein the polycyclic heterocycle is optionally substituted with 1 to 3 R 8 , a 5- to 12-membered polycyclic heterocyclyl, and each R 8 is independently selected from H, halogen, oxo, cyano, hydroxyl, NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl)2, COOH, C 1-6 alkyl, C 1-6 alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 alkylene-carbocyclyl, or C 1-6 alkylene-heteroaryl, L is polycyclic cycloalkylene, polycyclic arylene, or polycyclic heteroarylene, and the first atom of the first ring of the polycyclic arylene or polycyclic heteroarylene is [Chemical formula] connected to, and the second atom of the second ring of the polycyclic arylene or heteroarylene is connected to R 1 , wherein L is independently substituted by 0 to 4 R 10 , each R 10However, independently, =O, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, SC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1-6 Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CON 1-6 Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6 Alkyl or heterocyclic, where each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic ring is independently and optionally substituted with 1 to 3 substituents selected from halogens, cyano, hydroxyl, NH2, and COOH. R 1 but, ● 1 to 3 R g 5-12 member carbocyclils that are optionally substituted, ● 1 to 3 R g 6-18 member aryls that are optionally substituted, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocycline contains 1-3 R g A 5-12 member monocyclic heterocycline is optionally substituted in this case. ● A 5-12 member monocyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heteroaryl contains 1-3 R g 5-12 member monocyclic heteroaryls that are optionally substituted, ● A 7-14 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the bicyclic heteroaryl contains 1-4 R g A 7-14 member bicyclic heteroaryl, which is optionally substituted, or ● A 7-20 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the tricyclic heteroaryl contains 1-5 R g It is a 7-20 member tricyclic heteroaryl that is optionally substituted, Each R g However, independently, hydrogen, SF5, =O, halogen, cyano, hydroxyl, nitro, NH2, -COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 2-6 Alkenil, C 2-5 Alkinyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2,-COC 1-6 Alkyl, -COOC 1-6 Alkyl, -CONH2, -CONHC 1-6 Alkyl, -CONHC 3-6 Cycloalkyl, -CON(C 1-6 Alkyl)2,-NHCOC 1-6 Alkyl, -NHCOC 3-5 Cycloalkyl, -P(O)(C 1-6 Alkyl), -S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6 Cycloalkyl, -SO2-3~7 member heterocyclyl, -S(O)NH2, -S(O)NHC 1-6 Alkyl, -S(O)N(C) 1-6 Alkyl)2,-S(O)2NH2,-OSO2-C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 - A 3- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from cycloalkenyloxy, aryl, heteroaryl, N, S, and O, R g However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6-Alkylene-OH, -CONH2,NH2,C 1-6 Further optionally selected from alkoxy, hydroxyl, -COOH, halogen, or 1-3 groups selected from a 5-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, wherein the 5-7 membered heterocycle is =O, halogen, cyano, C 1-6 Alkyl, and C 1-6 The present invention provides compounds of formula (I), or pharmaceutically acceptable salts or deuterated forms thereof, which are optionally substituted with one or two groups selected from haloalkyl groups.

[0009] In embodiments, the present disclosure relates to a compound of formula (II), [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein the formula, R 0 but, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycle contains 1-3 R 8 A 5-12 member monocyclic heterocycline, which is optionally substituted, or ● A 5-12 membered polycyclic heterocyclil containing 1-3 heteroatoms selected from N, S, and O, wherein the polycyclic heterocycle contains 1-3 R 8 It is a 5-12 member polycyclic heterocycline that is optionally substituted, Each R 8 However, independently, H, halogen, oxo, cyano, hydroxyl, NH2, NH(C) 1-6 Alkyl), N(C 1-6 Alkyl)2, COOH, C 1-6 Alkyl, C 1-6 Alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6 Alkoxy, C halogenated 1-6 Alkoxy, C 1-6 Alkilen-carbocykrill, or C 1-6 Selected from alkylene heteroaryls, R1 is ● 5- to 12-membered carbocyclic optionally substituted with 1 to 3 R g groups, ● 6- to 18-membered aryl optionally substituted with 1 to 3 R g groups, ● 5- to 12-membered monocyclic heterocyclyl containing 1 to 3 heteroatoms selected from N, S, or O, the monocyclic heterocyclyl being optionally substituted with 1 to 3 R g groups, ● 5- to 12-membered monocyclic heteroaryl containing 1 to 3 heteroatoms selected from N, S, or O, the monocyclic heteroaryl being optionally substituted with 1 to 3 R g groups, ● 7- to 14-membered bicyclic heteroaryl containing​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​1-6 Alkyl, -CONHC 3-6 Cycloalkyl, -CON(C 1-6 Alkyl)2,-NHCOC 1-6 Alkyl, -NHCOC 3-5 Cycloalkyl, -P(O)(C 1-6 Alkyl), -S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6 Cycloalkyl, -SO2-3~7 member heterocyclyl, -S(O)NH2, -S(O)NHC 1-6 Alkyl, -S(O)N(C) 1-6 Alkyl)2,-S(O)2NH2,-OSO2-C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 - A 3- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from cycloalkenyloxy, aryl, heteroaryl, N, S, and O, R g However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 -Alkylene-OH, -CONH2,NH2,C 1-6 Further optionally substituted with 1 to 3 groups selected from a 5-7 membered heterocycle containing alkoxy, hydroxyl, -COOH, halogen, or N, S, and O, wherein the 5-7 membered heterocycle is =O, halogen, cyano, C 1-6 Alkyl, and C 1-6 The present invention provides compounds of formula (II), or pharmaceutically acceptable salts or deuterated forms thereof, which are optionally substituted with one or two groups selected from haloalkyl groups.

[0010] This disclosure relates to a compound of formula (III), [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein the formula, R 0 but, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycle contains 1-3 R 8 A 5-12 member monocyclic heterocycline, which is optionally substituted, or ● A 5-12 membered polycyclic heterocyclil containing 1-3 heteroatoms selected from N, S, and O, wherein the polycyclic heterocycle contains 1-3 R 8 It is a 5-12 member polycyclic heterocycline that is optionally substituted, Each R 8 However, independently, H, halogen, oxo, cyano, hydroxyl, NH2, NH(C) 1-6 Alkyl), N(C 1-6 Alkyl)2, COOH, C 1-6 Alkyl, C 1-6 Alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6 Alkoxy, C halogenated 1-6 Alkoxy, C 1-6 Alkilen-carbocykrill, or C 1-6 Selected from alkylene heteroaryls, R 1 but, ● 1 to 3 R g 5-12 member carbocyclils that are optionally substituted, ● 1 to 3 R g 6-18 member aryls that are optionally substituted, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocycline contains 1-3 R g A 5-12 member monocyclic heterocycline is optionally substituted in this case. ● A 5-12 member monocyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heteroaryl contains 1-3 R g 5-12 member monocyclic heteroaryls that are optionally substituted, ● A 7-14 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the bicyclic heteroaryl contains 1-4 Rg A 7-14 member bicyclic heteroaryl, which is optionally substituted, or ● A 7-20 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the tricyclic heteroaryl contains 1-5 R g It is a 7-20 member tricyclic heteroaryl that is optionally substituted, Each R g However, independently, hydrogen, SF5, =O, halogen, cyano, hydroxyl, nitro, NH2, -COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 2-6 Alkenil, C 2-5 Alkinyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2,-COC 1-6 Alkyl, -COOC 1-6 Alkyl, -CONH2, -CONHC 1-6 Alkyl, -CONHC 3-6 Cycloalkyl, -CON(C 1-6 Alkyl)2,-NHCOC 1-6 Alkyl, -NHCOC 3-5 Cycloalkyl, -P(O)(C 1-6 Alkyl), -S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6 Cycloalkyl, -SO2-3~7 member heterocyclyl, -S(O)NH2, -S(O)NHC 1-6 Alkyl, -S(O)N(C) 1-6 Alkyl)2,-S(O)2NH2,-OSO2-C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 - A 3- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from cycloalkenyloxy, aryl, heteroaryl, N, S, and O, R gHowever, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 -Alkylene-OH, -CONH2,NH2,C 1-6 Further optionally substituted with 1 to 3 groups selected from a 5-7 membered heterocycle containing alkoxy, hydroxyl, -COOH, halogen, or N, S, and O, wherein the 5-7 membered heterocycle is =O, halogen, cyano, C 1-6 Alkyl, and C 1-6 The present invention provides compounds of formula (III), or pharmaceutically acceptable salts or deuterated forms thereof, which are optionally substituted with one or two groups selected from haloalkyl groups.

[0011] In embodiments, the present disclosure relates to a compound of formula (IV), [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein the formula, R 0 but, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycle contains 1-3 R 8 A 5-12 member monocyclic heterocycline, which is optionally substituted, or ● A 5-12 membered polycyclic heterocyclil containing 1-3 heteroatoms selected from N, S, and O, wherein the polycyclic heterocycle contains 1-3 R 8 It is a 5-12 member polycyclic heterocycline that is optionally substituted, Each R 8 However, independently, H, halogen, oxo, cyano, hydroxyl, NH2, NH(C) 1-6 Alkyl), N(C 1-6 Alkyl)2, COOH, C 1-6 Alkyl, C 1-6 Alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6 Alkoxy, C halogenated 1-6 Alkoxy, C 1-6Alkilen-carbocykrill, or C 1-6 Selected from alkylene heteroaryls, R 1 but, ● 1 to 3 R g 5-12 member carbocyclils that are optionally substituted, ● 1 to 3 R g 6-18 member aryls that are optionally substituted, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocycline contains 1-3 R g A 5-12 member monocyclic heterocycline is optionally substituted in this case. ● A 5-12 member monocyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heteroaryl contains 1-3 R g 5-12 member monocyclic heteroaryls that are optionally substituted, ● A 7-14 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the bicyclic heteroaryl contains 1-4 R g A 7-14 member bicyclic heteroaryl, which is optionally substituted, or ● A 7-20 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the tricyclic heteroaryl contains 1-5 R g It is a 7-20 member tricyclic heteroaryl that is optionally substituted, Each R g However, independently, hydrogen, SF5, =O, halogen, cyano, hydroxyl, nitro, NH2, -COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 2-6 Alkenil, C 2-5 Alkinyl, -NHC 1-6 Alkyl, -N(C 1-6Alkyl)2,-COC 1-6 Alkyl, -COOC 1-6 Alkyl, -CONH2, -CONHC 1-6 Alkyl, -CONHC 3-6 Cycloalkyl, -CON(C 1-6 Alkyl)2,-NHCOC 1-6 Alkyl, -NHCOC 3-5 Cycloalkyl, -P(O)(C 1-6 Alkyl), -S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6 Cycloalkyl, -SO2-3~7 member heterocyclyl, -S(O)NH2, -S(O)NHC 1-6 Alkyl, -S(O)N(C) 1-6 Alkyl)2,-S(O)2NH2,-OSO2-C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 - A 3- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from cycloalkenyloxy, aryl, heteroaryl, N, S, and O, R g However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 -Alkylene-OH, -CONH2,NH2,C 1-6 Further optionally substituted with 1 to 3 groups selected from a 5-7 membered heterocycle containing alkoxy, hydroxyl, -COOH, halogen, or N, S, and O, wherein the 5-7 membered heterocycle is =O, halogen, cyano, C 1-6 Alkyl, and C 1-6 The present invention provides compounds of formula (IV), or pharmaceutically acceptable salts or deuterated forms thereof, which are optionally substituted with one or two groups selected from haloalkyl groups.

[0012] In embodiments, the present disclosure relates to a compound of formula (V), [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein the formula, R 0 but, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycle contains 1-3 R 8 A 5-12 member monocyclic heterocycline, which is optionally substituted, or ● A 5-12 membered polycyclic heterocyclil containing 1-3 heteroatoms selected from N, S, and O, wherein the polycyclic heterocycle contains 1-3 R 8 It is a 5-12 member polycyclic heterocycline that is optionally substituted, Each R 8 However, independently, H, halogen, oxo, cyano, hydroxyl, NH2, NH(C) 1-6 Alkyl), N(C 1-6 Alkyl)2, COOH, C 1-6 Alkyl, C 1-6 Alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6 Alkoxy, C halogenated 1-6 Alkoxy, C 1-6 Alkilen-carbocykrill, or C 1-6 Selected from alkylene heteroaryls, R 1 but, ● 1 to 3 R g 5-12 member carbocyclils that are optionally substituted, ● 1 to 3 R g 6-18 member aryls that are optionally substituted, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocycline contains 1-3 R g A 5-12 member monocyclic heterocycline is optionally substituted in this case. ● A 5-12 member monocyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heteroaryl contains 1-3 R g 5-12 member monocyclic heteroaryls that are optionally substituted, ● A 7-14 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the bicyclic heteroaryl contains 1-4 R g A 7-14 member bicyclic heteroaryl, which is optionally substituted, or ● A 7-20 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the tricyclic heteroaryl contains 1-5 R g It is a 7-20 member tricyclic heteroaryl that is optionally substituted, Each R g However, independently, hydrogen, SF5, =O, halogen, cyano, hydroxyl, nitro, NH2, -COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 2-6 Alkenil, C 2-5 Alkinyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2,-COC 1-6 Alkyl, -COOC 1-6 Alkyl, -CONH2, -CONHC 1-6 Alkyl, -CONHC 3-6 Cycloalkyl, -CON(C 1-6 Alkyl)2,-NHCOC 1-6 Alkyl, -NHCOC 3-5 Cycloalkyl, -P(O)(C 1-6 Alkyl), -S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6 Cycloalkyl, -SO2-3~7 member heterocyclyl, -S(O)NH2, -S(O)NHC 1-6 Alkyl, -S(O)N(C) 1-6 Alkyl)2,-S(O)2NH2,-OSO2-C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C3-8 - A 3- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from cycloalkenyloxy, aryl, heteroaryl, N, S, and O, R g However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 -Alkylene-OH, -CONH2,NH2,C 1-6 Further optionally substituted with 1 to 3 groups selected from a 5-7 membered heterocycle containing alkoxy, hydroxyl, -COOH, halogen, or N, S, and O, wherein the 5-7 membered heterocycle is =O, halogen, cyano, C 1-6 Alkyl, and C 1-6 Optionally substituted with 1-2 groups selected from haloalkyl groups, n is 0 or 1, Each R 10 However, independently, =O, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, SC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1-6 Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CON 1-6 Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6 It is alkyl or heterocyclic, and each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic is independently optionally substituted with 1 to 3 substituents selected from halogen, cyano, hydroxyl, NH2, and COOH, R 10 The present invention provides a compound of formula (V), or a pharmaceutically acceptable salt or deuterated form thereof, in which the benzothienylene ring is substituted on the phenyl or thiophenyl ring.

[0013] In embodiments, the present disclosure relates to a compound of formula (VI), [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein the formula, R 0 but, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycle contains 1-3 R 8 A 5-12 member monocyclic heterocycline, which is optionally substituted, or ● A 5-12 membered polycyclic heterocyclil containing 1-3 heteroatoms selected from N, S, and O, wherein the polycyclic heterocycle contains 1-3 R 8 It is a 5-12 member polycyclic heterocycline that is optionally substituted, Each R 8 However, independently, H, halogen, oxo, cyano, hydroxyl, NH2, NH(C) 1-6 Alkyl), N(C 1-6 Alkyl)2, COOH, C 1-6 Alkyl, C 1-6 Alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6 Alkoxy, C halogenated 1-6 Alkoxy, C 1-6 Alkilen-carbocykrill, or C 1-6 Selected from alkylene heteroaryls, R 1 but, ● 1 to 3 R g 5-12 member carbocyclils that are optionally substituted, ● 1 to 3 R g 6-18 member aryls that are optionally substituted, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocycline contains 1-3 R g A 5-12 member monocyclic heterocycline is optionally substituted in this case. ● A 5-12 member monocyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heteroaryl contains 1-3 R g 5-12 member monocyclic heteroaryls that are optionally substituted, ● A 7-14 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the bicyclic heteroaryl contains 1-4 R g A 7-14 member bicyclic heteroaryl, which is optionally substituted, or ● A 7-20 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the tricyclic heteroaryl contains 1-5 R g It is a 7-20 member tricyclic heteroaryl that is optionally substituted, Each R g However, independently, hydrogen, SF5, =O, halogen, cyano, hydroxyl, nitro, NH2, -COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 2-6 Alkenil, C 2-5 Alkinyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2,-COC 1-6 Alkyl, -COOC 1-6 Alkyl, -CONH2, -CONHC 1-6 Alkyl, -CONHC 3-6 Cycloalkyl, -CON(C 1-6 Alkyl)2,-NHCOC 1-6 Alkyl, -NHCOC 3-5 Cycloalkyl, -P(O)(C 1-6 Alkyl), -S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6 Cycloalkyl, -SO2-3~7 member heterocyclyl, -S(O)NH2, -S(O)NHC 1-6Alkyl, -S(O)N(C) 1-6 Alkyl)2,-S(O)2NH2,-OSO2-C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 - A 3- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from cycloalkenyloxy, aryl, heteroaryl, N, S, and O, R g However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 -Alkylene-OH, -CONH2,NH2,C 1-6 Further optionally substituted with 1 to 3 groups selected from a 5-7 membered heterocycle containing alkoxy, hydroxyl, -COOH, halogen, or N, S, and O, wherein the 5-7 membered heterocycle is =O, halogen, cyano, C 1-6 Alkyl, and C 1-6 Optionally substituted with 1-2 groups selected from haloalkyl groups, n is 0 or 1, Each R 10 However, independently, =O, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, SC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1-6 Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CON 1-6 Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6 Alkyl or heterocyclic, where each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic ring is independently and optionally substituted with 1 to 3 substituents selected from halogen, cyano, hydroxyl, NH2, and COOH, R 10The present invention provides a compound of formula (VI), or a pharmaceutically acceptable salt or deuterated form thereof, in which the benzothienylene ring is substituted on the phenyl or thiophenyl ring.

[0014] In embodiments, the present disclosure relates to a compound of formula (VII), [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein the formula, R 0 but, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycle contains 1-3 R 8 A 5-12 member monocyclic heterocycline, which is optionally substituted, or ● A 5-12 membered polycyclic heterocyclil containing 1-3 heteroatoms selected from N, S, and O, wherein the polycyclic heterocycle contains 1-3 R 8 It is a 5-12 member polycyclic heterocycline that is optionally substituted, Each R 8 However, independently, H, halogen, oxo, cyano, hydroxyl, NH2, NH(C) 1-6 Alkyl), N(C 1-6 Alkyl)2, COOH, C 1-6 Alkyl, C 1-6 Alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6 Alkoxy, C halogenated 1-6 Alkoxy, C 1-6 Alkilen-carbocykrill, or C 1-6 Selected from alkylene heteroaryls, R 1 but, ● 1 to 3 R g 5-12 member carbocyclils that are optionally substituted, ● 1 to 3 R g 6-18 member aryls that are optionally substituted, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocycline contains 1-3 R g A 5-12 member monocyclic heterocycline is optionally substituted in this case. ● A 5-12 member monocyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heteroaryl contains 1-3 R g 5-12 member monocyclic heteroaryls that are optionally substituted, ● A 7-14 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the bicyclic heteroaryl contains 1-4 R g A 7-14 member bicyclic heteroaryl, which is optionally substituted, or ● A 7-20 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the tricyclic heteroaryl contains 1-5 R g It is a 7-20 member tricyclic heteroaryl that is optionally substituted, Each R g However, independently, hydrogen, SF5, =O, halogen, cyano, hydroxyl, nitro, NH2, -COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 2-6 Alkenil, C 2-5 Alkinyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2,-COC 1-6 Alkyl, -COOC 1-6 Alkyl, -CONH2, -CONHC 1-6 Alkyl, -CONHC 3-6 Cycloalkyl, -CON(C 1-6 Alkyl)2,-NHCOC 1-6 Alkyl, -NHCOC 3-5 Cycloalkyl, -P(O)(C 1-6Alkyl), -S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6 Cycloalkyl, -SO2-3~7 member heterocyclyl, -S(O)NH2, -S(O)NHC 1-6 Alkyl, -S(O)N(C) 1-6 Alkyl)2,-S(O)2NH2,-OSO2-C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 - A 3- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from cycloalkenyloxy, aryl, heteroaryl, N, S, and O, R g However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 -Alkylene-OH, -CONH2,NH2,C 1-6 Further optionally substituted with 1 to 3 groups selected from a 5-7 membered heterocycle containing alkoxy, hydroxyl, -COOH, halogen, or N, S, and O, wherein the 5-7 membered heterocycle is =O, halogen, cyano, C 1-6 Alkyl, and C 1-6 Optionally substituted with 1-2 groups selected from haloalkyl groups, n is 0 or 1, Each R 10 However, independently, =O, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, SC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1-6 Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CON 1-6 Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6It is alkyl or heterocyclic, and each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic is independently optionally substituted with 1 to 3 substituents selected from halogen, cyano, hydroxyl, NH2, and COOH, R 10 The present invention provides a compound of formula (VII), or a pharmaceutically acceptable salt or deuterated form thereof, in which the benzothienylene ring is substituted on the phenyl or thiophenyl ring.

[0015] In embodiments, the present disclosure relates to a compound of formula (XIV), [ka] or a pharmaceutically acceptable salt or deuterated form thereof, in the formula, R 0 but, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycle contains 1-3 R 8 A 5-12 member monocyclic heterocycline, which is optionally substituted, or ● A 5-12 membered polycyclic heterocyclil containing 1-3 heteroatoms selected from N, S, and O, wherein the polycyclic heterocycle contains 1-3 R 8 It is a 5-12 member polycyclic heterocycline that is optionally substituted, Each R 8 However, independently, H, halogen, oxo, cyano, hydroxyl, NH2, NH(C) 1-6 Alkyl), N(C 1-6 Alkyl)2, COOH, C 1-6 Alkyl, C 1-6 Alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6 Alkoxy, C halogenated 1-6 Alkoxy, C 1-6 Alkilen-carbocykrill, or C 1-6 Selected from alkylene heteroaryls, R 1 but, ● 1 to 3 R g5-12 member carbocyclils that are optionally substituted, ● 1 to 3 R g 6-18 member aryls that are optionally substituted, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocycline contains 1-3 R g A 5-12 member monocyclic heterocycline is optionally substituted in this case. ● A 5-12 member monocyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heteroaryl contains 1-3 R g 5-12 member monocyclic heteroaryls that are optionally substituted, ● A 7-14 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the bicyclic heteroaryl contains 1-4 R g A 7-14 member bicyclic heteroaryl, which is optionally substituted, or ● A 7-20 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the tricyclic heteroaryl contains 1-5 R g It is a 7-20 member tricyclic heteroaryl that is optionally substituted at the base, Each R g However, independently, hydrogen, SF5, =O, halogen, cyano, hydroxyl, nitro, NH2, -COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 2-6 Alkenil, C 2-5 Alkinyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2,-COC 1-6 Alkyl, -COOC 1-6 Alkyl, -CONH2, -CONHC 1-6 Alkyl, -CONHC 3-6 Cycloalkyl, -CON(C1-6 Alkyl)2,-NHCOC 1-6 Alkyl, -NHCOC 3-5 Cycloalkyl, -P(O)(C 1-6 Alkyl), -S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6 Cycloalkyl, -SO2-3~7 member heterocyclyl, -S(O)NH2, -S(O)NHC 1-6 Alkyl, -S(O)N(C) 1-6 Alkyl)2,-S(O)2NH2,-OSO2-C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 - A 3- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from cycloalkenyloxy, aryl, heteroaryl, N, S, and O, R g However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 -Alkylene-OH, -CONH2,NH2,C 1-6 Further optionally substituted with 1 to 3 groups selected from a 5-7 membered heterocycle containing alkoxy, hydroxyl, -COOH, halogen, or N, S, and O, wherein the 5-7 membered heterocycle is =O, halogen, cyano, C 1-6 Alkyl, and C 1-6 Optionally substituted with 1-2 groups selected from haloalkyl groups, n is 0 or 1, Each R 10 However, independently, =O, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, SC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1-6 Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CON1-6 Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6 It is alkyl or heterocyclic, and each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic is independently optionally substituted with 1 to 3 substituents selected from halogen, cyano, hydroxyl, NH2, and COOH, R 10 The present invention provides a compound of formula (XIV), or a pharmaceutically acceptable salt or deuterated form thereof, in which the benzothienylene ring is substituted on the phenyl or thiophenyl ring.

[0016] In embodiments, the present disclosure relates to a compound of formula (VIII), [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein the formula, R 0 but, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycle contains 1-3 R 8 A 5-12 member monocyclic heterocycline, which is optionally substituted, or ● A 5-12 membered polycyclic heterocyclil containing 1-3 heteroatoms selected from N, S, and O, wherein the polycyclic heterocycle contains 1-3 R 8 It is a 5-12 member polycyclic heterocycline that is optionally substituted, Each R 8 However, independently, H, halogen, oxo, cyano, hydroxyl, NH2, NH(C) 1-6 Alkyl), N(C 1-6 Alkyl)2, COOH, C 1-6 Alkyl, C 1-6 Alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6 Alkoxy, C halogenated 1-6 Alkoxy, C 1-6 Alkilen-carbocykrill, or C 1-6 Selected from alkylene heteroaryls, R 1 but, ● 1 to 3 R g 5-12 member carbocyclils that are optionally substituted, ● 1 to 3 R g 6-18 member aryls that are optionally substituted, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocycline contains 1-3 R g A 5-12 member monocyclic heterocycline is optionally substituted in this case. ● A 5-12 member monocyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heteroaryl contains 1-3 R g 5-12 member monocyclic heteroaryls that are optionally substituted, ● A 7-14 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the bicyclic heteroaryl contains 1-4 R g A 7-14 member bicyclic heteroaryl, which is optionally substituted, or ● A 7-20 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the tricyclic heteroaryl contains 1-5 R g It is a 7-20 member tricyclic heteroaryl that is optionally substituted, Each R g However, independently, hydrogen, SF5, =O, halogen, cyano, hydroxyl, nitro, NH2, -COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 2-6 Alkenil, C 2-5 Alkinyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2,-COC 1-6 Alkyl, -COOC 1-6Alkyl, -CONH2, -CONHC 1-6 Alkyl, -CONHC 3-6 Cycloalkyl, -CON(C 1-6 Alkyl)2,-NHCOC 1-6 Alkyl, -NHCOC 3-5 Cycloalkyl, -P(O)(C 1-6 Alkyl), -S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6 Cycloalkyl, -SO2-3~7 member heterocyclyl, -S(O)NH2, -S(O)NHC 1-6 Alkyl, -S(O)N(C) 1-6 Alkyl)2,-S(O)2NH2,-OSO2-C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 - A 3- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from cycloalkenyloxy, aryl, heteroaryl, N, S, and O, R g However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 -Alkylene-OH, -CONH2,NH2,C 1-6 Further optionally substituted with 1 to 3 groups selected from a 5-7 membered heterocycle containing alkoxy, hydroxyl, -COOH, halogen, or N, S, and O, wherein the 5-7 membered heterocycle is =O, halogen, cyano, C 1-6 Alkyl, and C 1-6 Optionally substituted with 1-2 groups selected from haloalkyl groups, n is 0 or 1, Each R 10 However, independently, =O, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, SC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1-6 Alkyl, N(C1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CON 1-6 Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6 The present invention provides compounds of formula (VIII), or pharmaceutically acceptable salts or deuterated forms thereof, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic ring is independently and optionally substituted with 1 to 3 substituents selected from halogens, cyano, hydroxyl, NH2, and COOH.

[0017] In embodiments, the present disclosure relates to a compound of formula (IX), [ka] or a pharmaceutically acceptable salt or deuterated form thereof, R 0 but, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycle contains 1-3 R 8 A 5-12 member monocyclic heterocycline, which is optionally substituted, or ● A 5-12 membered polycyclic heterocyclil containing 1-3 heteroatoms selected from N, S, and O, wherein the polycyclic heterocycle contains 1-3 R 8 It is a 5-12 member polycyclic heterocycline that is optionally substituted, Each R 8 However, independently, H, halogen, oxo, cyano, hydroxyl, NH2, NH(C) 1-6 Alkyl), N(C 1-6 Alkyl)2, COOH, C 1-6 Alkyl, C 1-6 Alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6 Alkoxy, C halogenated 1-6 Alkoxy, C 1-6 Alkilen-carbocykrill, or C 1-6Selected from alkylene heteroaryls, Each R 6 However, independently, H, C 1-6 Alkyl, -COC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl and C 3-6 Selected from cycloalkyl groups, alkyl, alkenyl, alkynyl, and cycloalkyl groups are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH. Each R 7 However, independently, H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CONHC 1-6 Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6 Selected from alkyl and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, or O, R 7 The present invention provides compounds of formula (IX), or pharmaceutically acceptable salts or deuterated forms thereof, in which the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups within the formula are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH.

[0018] In embodiments, the present disclosure relates to a compound of formula (X), [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein the formula, R 0 but, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycle contains 1-3 R 8 A 5-12 member monocyclic heterocycline, which is optionally substituted, or ● A 5-12 membered polycyclic heterocyclil containing 1-3 heteroatoms selected from N, S, and O, wherein the polycyclic heterocycle contains 1-3 R 8 It is a 5-12 member polycyclic heterocycline that is optionally substituted, Each R 8 However, independently, H, halogen, oxo, cyano, hydroxyl, NH2, NH(C) 1-6 Alkyl), N(C 1-6 Alkyl)2, COOH, C 1-6 Alkyl, C 1-6 Alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6 Alkoxy, C halogenated 1-6 Alkoxy, C 1-6 Alkilen-carbocykrill, or C 1-6 Selected from alkylene heteroaryls, Each R 6 However, independently, H, C 1-6 Alkyl, -COC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl and C 3-6 Selected from cycloalkyl groups, alkyl, alkenyl, alkynyl, and cycloalkyl groups are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH. Each R 7 However, independently, H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6Alkyl, CONHC 1-6 Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6 Selected from alkyl and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, or O, R 7 The present invention provides compounds of formula (X), or pharmaceutically acceptable salts or deuterated forms thereof, in which the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups within the formula are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH.

[0019] In embodiments, the present disclosure relates to a compound of formula (XI), [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein the formula, R 0 but, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycle contains 1-3 R 8 A 5-12 member monocyclic heterocycline, which is optionally substituted, or ● A 5-12 membered polycyclic heterocyclil containing 1-3 heteroatoms selected from N, S, and O, wherein the polycyclic heterocycle contains 1-3 R 8 It is a 5-12 member polycyclic heterocycline that is optionally substituted, Each R 8 However, independently, H, halogen, oxo, cyano, hydroxyl, NH2, NH(C) 1-6 Alkyl), N(C 1-6 Alkyl)2, COOH, C 1-6 Alkyl, C 1-6 Alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6 Alkoxy, C halogenated 1-6 Alkoxy, C 1-6 Alkilen-carbocykrill, or C 1-6 Selected from alkylene heteroaryls, Each R 6 However, independently, H, C 1-6 Alkyl, -COC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl and C 3-6 Selected from cycloalkyl groups, alkyl, alkenyl, alkynyl, and cycloalkyl groups are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH. Each R 7 However, independently, H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CONHC 1-6 Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6 Selected from alkyl and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, or O, R 7 The alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups within are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH. n is 0 or 1, Each R 10 However, independently, =O, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, SC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1-6 Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CON1-6 Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6 It is alkyl or heterocyclic, and each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic is independently optionally substituted with 1 to 3 substituents selected from halogen, cyano, hydroxyl, NH2, and COOH, R 10 The present invention provides a compound of formula (XI), or a pharmaceutically acceptable salt or deuterated form thereof, in which the benzothienylene ring is substituted on the phenyl or thiophenyl ring.

[0020] In embodiments, the present disclosure relates to a compound of formula (XII), [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 0 but, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycle contains 1-3 R 8 A 5-12 member monocyclic heterocycline, which is optionally substituted, or ● A 5-12 membered polycyclic heterocyclil containing 1-3 heteroatoms selected from N, S, and O, wherein the polycyclic heterocycle contains 1-3 R 8 It is a 5-12 member polycyclic heterocycline that is optionally substituted, Each R 8 However, independently, H, halogen, oxo, cyano, hydroxyl, NH2, NH(C) 1-6 Alkyl), N(C 1-6 Alkyl)2, COOH, C 1-6 Alkyl, C 1-6 Alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6 Alkoxy, C halogenated 1-6 Alkoxy, C 1-6 Alkilen-carbocykrill, or C 1-6 Selected from alkylene heteroaryls, Each R6 However, independently, H, C 1-6 Alkyl, -COC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl and C 3-6 Selected from cycloalkyl groups, alkyl, alkenyl, alkynyl, and cycloalkyl groups are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH. Each R 7 However, independently, H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CONHC 1-6 Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6 Selected from alkyl and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, or O, R 7 The alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups within are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH. n is 0 or 1, Each R 10 However, independently, =O, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, SC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1-6 Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CON 1-6Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6 It is alkyl or heterocyclic, and each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic is independently optionally substituted with 1 to 3 substituents selected from halogen, cyano, hydroxyl, NH2, and COOH, R 10 The present invention provides a compound of formula (XII), or a pharmaceutically acceptable salt or deuterated form thereof, in which the benzothienylene ring is substituted on the phenyl or thiophenyl ring.

[0021] In embodiments, the present disclosure relates to a compound of formula (XIII), [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 0 but, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycle contains 1-3 R 8 A 5-12 member monocyclic heterocycline, which is optionally substituted, or ● A 5-12 membered polycyclic heterocyclil containing 1-3 heteroatoms selected from N, S, and O, wherein the polycyclic heterocycle contains 1-3 R 8 It is a 5-12 member polycyclic heterocycline that is optionally substituted, Each R 8 However, independently, H, halogen, oxo, cyano, hydroxyl, NH2, NH(C) 1-6 Alkyl), N(C 1-6 Alkyl)2, COOH, C 1-6 Alkyl, C 1-6 Alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6 Alkoxy, C halogenated 1-6 Alkoxy, C 1-6 Alkilen-carbocykrill, or C 1-6 Selected from alkylene heteroaryls, Each R 6However, independently, H, C 1-6 Alkyl, -COC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl and C 3-6 Selected from cycloalkyl groups, alkyl, alkenyl, alkynyl, and cycloalkyl groups are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH. Each R 7 However, independently, H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CONHC 1-6 Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6 Selected from alkyl and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, or O, R 7 The alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups within are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH. n is 0 or 1, Each R 10 However, independently, =O, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, SC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1-6 Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CON 1-6 Alkyl, CON(C1-6 Alkyl)2, NHCOC 1-6 It is alkyl or heterocyclic, and each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic is independently optionally substituted with 1 to 3 substituents selected from halogen, cyano, hydroxyl, NH2, and COOH, R 10 The present invention provides a compound of formula (XIII), or a pharmaceutically acceptable salt or deuterated form thereof, in which the benzothienylene ring is substituted on the phenyl or thiophenyl ring.

[0022] In embodiments, the present disclosure relates to a compound of formula (XV), [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein the formula, R 0 but, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycle contains 1-3 R 8 A 5-12 member monocyclic heterocycline, which is optionally substituted, or ● A 5-12 membered polycyclic heterocyclil containing 1-3 heteroatoms selected from N, S, and O, wherein the polycyclic heterocycle contains 1-3 R 8 It is a 5-12 member polycyclic heterocycline that is optionally substituted, Each R 8 However, independently, H, halogen, oxo, cyano, hydroxyl, NH2, NH(C) 1-6 Alkyl), N(C 1-6 Alkyl)2, COOH, C 1-6 Alkyl, C 1-6 Alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6 Alkoxy, C halogenated 1-6 Alkoxy, C 1-6 Alkilen-carbocykrill, or C 1-6 Selected from alkylene heteroaryls, Each R 6However, independently, H, C 1-6 Alkyl, -COC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl and C 3-6 Selected from cycloalkyl groups, alkyl, alkenyl, alkynyl, and cycloalkyl groups are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH. Each R 7 However, independently, H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CONHC 1-6 Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6 Selected from alkyl and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, or O, R 7 The alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups within are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH. n is 0 or 1, Each R 10 However, independently, =O, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, SC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1-6 Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CON 1-6 Alkyl, CON(C1-6 Alkyl)2, NHCOC 1-6 Alkyl or heterocyclic, where each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic ring is independently and optionally substituted with 1 to 3 substituents selected from halogen, cyano, hydroxyl, NH2, and COOH, R 10 The present invention provides a compound of formula (XV), or a pharmaceutically acceptable salt or deuterated form thereof, in which the benzothienylene ring is substituted on the phenyl or thiophenyl ring.

[0023] In embodiments, the present disclosure relates to a compound of formula (XVI), [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein the formula, R 0 but, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycle contains 1-3 R 8 A 5-12 member monocyclic heterocycline, which is optionally substituted, or ● A 5-12 membered polycyclic heterocyclil containing 1-3 heteroatoms selected from N, S, and O, wherein the polycyclic heterocycle contains 1-3 R 8 It is a 5-12 member polycyclic heterocycline that is optionally substituted, Each R 8 However, independently, H, halogen, oxo, cyano, hydroxyl, NH2, NH(C) 1-6 Alkyl), N(C 1-6 Alkyl)2, COOH, C 1-6 Alkyl, C 1-6 Alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6 Alkoxy, C halogenated 1-6 Alkoxy, C 1-6 Alkilen-carbocykrill, or C 1-6 Selected from alkylene heteroaryls, Each R 6However, independently, H, C 1-6 Alkyl, -COC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl and C 3-6 Selected from cycloalkyl groups, alkyl, alkenyl, alkynyl, and cycloalkyl groups are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH. Each R 7 However, independently, H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CONHC 1-6 Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6 Selected from alkyl and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, or O, R 7 The alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups within are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH. Each of rings E and F is a 5-membered heteroarylene ring. n is 0 or 1, Each R 10 However, independently, =O, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, SC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1-6 Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC1-6 Alkyl, CON 1-6 Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6 Alkyl or heterocyclic, where each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic ring is independently and optionally substituted with 1 to 3 substituents selected from halogen, cyano, hydroxyl, NH2, and COOH, R 10 The present invention provides a compound of formula (XVI), or a pharmaceutically acceptable salt or deuterated form thereof, in which ring E or ring F is substituted.

[0024] In embodiments, the present disclosure relates to a compound of formula (XVII), [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein the formula, R 0 but, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycle contains 1-3 R 8 A 5-12 member monocyclic heterocycline, which is optionally substituted, or ● A 5-12 membered polycyclic heterocyclil containing 1-3 heteroatoms selected from N, S, and O, wherein the polycyclic heterocycle contains 1-3 R 8 It is a 5-12 member polycyclic heterocycline that is optionally substituted, Each R 8 However, independently, H, halogen, oxo, cyano, hydroxyl, NH2, NH(C) 1-6 Alkyl), N(C 1-6 Alkyl)2, COOH, C 1-6 Alkyl, C 1-6 Alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6 Alkoxy, C halogenated 1-6 Alkoxy, C 1-6 Alkilen-carbocykrill, or C 1-6 Selected from alkylene heteroaryls, Each R 6 is independently selected from H, C 1-6 alkyl, -COC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl, and alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH; Each R 7 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, cyano, hydroxyl, NH2, NHC 1-6 alkyl, N(C 1-6 alkyl)2, COOH, COC 1-6 alkyl, COOC 1-6 alkyl, CONHC 1-6 alkyl, CON(C 1-6 alkyl)2, NHCOC 1-6 alkyl, and a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, or O, and the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups within R 7 are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH; X’ is O, S, NH, or N(C 1-6 alkyl); n is 0 or 1; Each R 10 is independently =O, halogen, C 1-6 alkyl, C 1-6 alkoxy, S-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, cyano, hydroxy, NH2, -NH-C 1-6 alkyl, N(C 1-6Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CON 1-6 Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6 Alkyl or heterocyclic, where each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic ring is independently optionally substituted with 1 to 3 substituents selected from halogen, cyano, hydroxyl, NH2, and COOH, R 10 but, [ka] The present invention provides a compound of formula (XVII) substituted on a phenyl ring or a five-membered ring, or a pharmaceutically acceptable salt or deuterated form thereof.

[0025] In embodiments, this disclosure relates to a compound of formula (XVIII), [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein the formula, R 0 but, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycle contains 1-3 R 8 A 5-12 member monocyclic heterocycline, which is optionally substituted, or ● A 5-12 membered polycyclic heterocyclil containing 1-3 heteroatoms selected from N, S, and O, wherein the polycyclic heterocycle contains 1-3 R 8 It is a 5-12 member polycyclic heterocycline that is optionally substituted, Each R 8 However, independently, H, halogen, oxo, cyano, hydroxyl, NH2, NH(C) 1-6 Alkyl), N(C 1-6 Alkyl)2, COOH, C 1-6 Alkyl, C 1-6Alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6 Alkoxy, C halogenated 1-6 Alkoxy, C 1-6 Alkilen-carbocykrill, or C 1-6 Selected from alkylene heteroaryls, Each R 6 However, independently, H, C 1-6 Alkyl, -COC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl and C 3-6 Selected from cycloalkyl groups, alkyl, alkenyl, alkynyl, and cycloalkyl groups are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH. Each R 7 However, independently, H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CONHC 1-6 Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6 Selected from alkyl and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, or O, R 7 The alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups within are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH. X' is O, S, NH, or N(C 1-6 It is alkyl, n is 0 or 1, Each R 10 However, independently, =O, halogen, C 1-6 Alkyl, C 1-6Alkoxy, S-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1-6 Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CON 1-6 Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6 Alkyl, or a heterocyclic ring, and each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic ring is independently optionally substituted with 1 to 3 substituents selected from halogen, cyano, hydroxyl, NH2, and COOH, R 10 is

Chemical formula

[0026] In an embodiment, the present disclosure is a compound of formula (XIX),

Chemical formula

[0027] In embodiments, the present disclosure relates to a compound of formula (XX), [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein the formula, R 0 but, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, and O, wherein the monocyclic heterocycle contains 1-3 R 8 A 5-12 member monocyclic heterocycline, which is optionally substituted, or ● A 5-12 membered polycyclic heterocyclil containing 1-3 heteroatoms selected from N, S, and O, wherein the polycyclic heterocycle contains 1-3 R 8It is a 5-12 member polycyclic heterocycline that is optionally substituted, Each R 8 However, independently, H, halogen, oxo, cyano, hydroxyl, NH2, NH(C) 1-6 Alkyl), N(C 1-6 Alkyl)2, COOH, C 1-6 Alkyl, C 1-6 Alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6 Alkoxy, C halogenated 1-6 Alkoxy, C 1-6 Alkilen-carbocykrill, or C 1-6 Selected from alkylene heteroaryls, Each R 6 However, independently, H, C 1-6 Alkyl, -COC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl and C 3-6 Selected from cycloalkyl groups, alkyl, alkenyl, alkynyl, and cycloalkyl groups are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH. Each R 7 However, independently, H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CONHC 1-6 Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6 Selected from alkyl and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, or O, R 7The alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups within are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH. n is 0 or 1, Each R 10 However, independently, =O, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, SC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1-6 Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CON 1-6 Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6 Alkyl or heterocyclic, where each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic ring is independently and optionally substituted with 1 to 3 substituents selected from halogen, cyano, hydroxyl, NH2, and COOH, R 10 but, [ka] The present invention provides compounds of formula (XX) substituted on the phenyl ring or thiophene ring, or pharmaceutically acceptable salts or deuterated forms thereof.

[0028] In embodiments, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein (for example, a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or a pharmaceutically acceptable salt or deuterated form thereof) and a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0029] In yet another aspect of this disclosure, a method of treatment is provided. In an embodiment, the method of treatment involves administering to a subject in need of treatment an effective amount of a composition comprising a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or a pharmaceutically acceptable salt or deuterated form thereof.

[0030] In one embodiment, the treatment method is a method for treating obstructive airway diseases, such as cystic fibrosis (CF), asthma, or bronchiectasis (e.g., non-CF bronchiectasis). In another embodiment, the treatment method is a method for treating chronic sinusitis (CRS).

[0031] In some embodiments, the treatment method is a method for treating sweat gland abscesses (HS).

[0032] In some embodiments, the treatment method is a method for treating cancer.

[0033] In some embodiments, the treatment method is a method for treating lupus nephritis.

[0034] In some embodiments, the treatment method is a method for treating rheumatoid arthritis.

[0035] In some embodiments, the treatment method is a method for treating inflammatory bowel disease (IBD). [Modes for carrying out the invention]

[0036] Throughout this disclosure, various patents, patent applications, and publications are referenced. To more fully describe the latest technology known to those skilled in the art as of the date of this disclosure, the entirety of these patents, patent applications, and publications is incorporated into this disclosure by reference for all purposes. In the event of any conflict between the cited patents, patent applications, and publications and this disclosure, this disclosure shall prevail.

[0037] definition The definitions of various terms used herein and in the claims to illustrate this disclosure are listed below.

[0038] Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meanings as those commonly understood by those skilled in the art to which this disclosure pertains.

[0039] The term “approximately” preceding a number means a range that includes plus or minus (e.g., plus or minus 10%) of the number, which is a permissible variation in the art. Unless the context of this disclosure indicates otherwise, or unless such interpretation is inconsistent, for example, “approximately 50” could mean 45 to 55, and “approximately 25,000” could mean 22,500 to 27,500, and so on. For example, in a list of numbers such as “approximately 49, approximately 50, approximately 55, ...”, “approximately 50” means a range that extends to less than half the interval (maybe one) between the preceding and succeeding numbers, for example, a range greater than 49.5 and less than 50.5. Furthermore, the phrases “less than approximately” or “greater than approximately” should be understood in consideration of the definition of the term “approximately” provided herein. Similarly, the term “approximately” preceding a series of numbers or ranges of values ​​(e.g., “approximately 10, 20, 30” or “approximately 10 to 30”) refers to all values ​​in the series or the endpoint of the range, respectively.

[0040] As used herein, the following terms have the meanings set forth below, unless otherwise indicated.

[0041] "Cyano" refers to the -CN radical.

[0042] "Hydroxy" or "hydroxyl" refers to the -OH radical.

[0043] "Oxo" refers to an =O substituent.

[0044] "Alkyl" or "alkyl group" refers to a fully saturated, linear or branched hydrocarbon chain radical having 1 to 12 carbon atoms bonded to the rest of the molecule by single bonds. Alkyl groups containing any number of carbon atoms from 1 to 12 are included. Alkyl groups containing up to 12 carbon atoms are C1-C 12 Alkyl atoms, which are alkyl groups containing up to 10 carbon atoms, are C1-C 10 Alkyls containing up to six carbon atoms are C1-C6 alkyls, and alkyls containing up to five carbon atoms are C1-C5 alkyls. C1-C5 alkyls include C5 alkyls, C4 alkyls, C3 alkyls, C2 alkyls, and C1 alkyls. C1-C6 alkyls include all the parts described above for C1-C5 alkyls, but also include C6 alkyls. 10 Alkyl includes all the parts described above for C1-C5 alkyl and C1-C6 alkyl, but also C7, C8, C9, and C 10 It also includes alkyl groups. Similarly, C1-C 12 Alkyl includes all of the aforementioned parts, but C 11 and C 12 Includes alkyl groups. C1-C 12 Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless otherwise specified herein, alkyl groups may be optionally substituted.

[0045] "Alkylene" or "alkylene chain" refers to a fully saturated, straight or branched divalent hydrocarbon chain radical having 1 to 12 carbon atoms. C1-C12 Non-limiting examples of alkylenes include methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, and n-butynylene. Alkylene chains connect to the rest of the molecule via single bonds and to radical groups via single bonds. The connection points of the alkylene chain to the rest of the molecule and radical groups can be via one carbon or any two carbons within the chain. Unless otherwise specified herein, alkylene chains may be optionally substituted.

[0046] An "alkenyl" or "alkenyl group" refers to a linear or branched hydrocarbon chain radical having 2 to 12 carbon atoms and one or more carbon-carbon double bonds. Each alkenyl group is bonded to the rest of the molecule by a single bond. Alkenyl groups containing any number of carbon atoms from 2 to 12 are included. Alkenyl groups containing up to 12 carbon atoms are C2-C 12 Alkenyls are alkenyl groups containing up to 10 carbon atoms, C2-C 10 Alkenyl groups containing up to six carbon atoms are C2-C6 alkenyls, and alkenyl groups containing up to five carbon atoms are C2-C5 alkenyls. C2-C5 alkenyls include C5 alkenyls, C4 alkenyls, C3 alkenyls, and C2 alkenyls. C2-C6 alkenyls include all the parts described above for C2-C5 alkenyls, but also include C6 alkenyls. 10 Alkenyls include all the parts described above for C2-C5 alkenyls and C2-C6 alkenyls, but also C7, C8, C9, and C 10 This also includes alkenyls. Similarly, C2-C 12 Alkenil includes all of the aforementioned parts, but C 11 and C 12 Includes alkenyls. C2-C 12Non-limiting examples of alkenyls include etenyl(vinyl), 1-propenyl, 2-propenyl(allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl Examples include 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl. Unless otherwise specified herein, alkenyl groups may be optionally substituted.

[0047] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain radical having 2 to 12 carbon atoms and one or more carbon-carbon double bonds. C2-C 12 Non-limiting examples of alkenylenes include ethene, propene, and butene. Alkenylene chains connect to the rest of the molecule via single bonds and to radical groups via single bonds. The connection points of the alkenylene chain to the rest of the molecule and radical groups can be via one carbon or any two carbons within the chain. Unless otherwise specified herein, alkenylene chains may be optionally substituted.

[0048] An "alkynyl" or "alkynyl group" refers to a linear or branched hydrocarbon chain radical having 2 to 12 carbon atoms and one or more carbon-carbon triple bonds. Each alkynyl group is bonded to the rest of the molecule by a single bond. Alkynyl groups containing any number of carbon atoms from 2 to 12 are included. Alkynyl groups containing up to 12 carbon atoms are C2-C 12 Alkynnyl groups, which contain up to 10 carbon atoms, are C2-C 10 Alkynnyl groups containing up to six carbon atoms are C2-C6 alkynyls, and alkynyl groups containing up to five carbon atoms are C2-C5 alkynyls. C2-C5 alkynyls include C5 alkynyls, C4 alkynyls, C3 alkynyls, and C2 alkynyls. C2-C6 alkynyls include all the parts described above for C2-C5 alkynyls, but also include C6 alkynyls. 10 Alkynnyl includes all the parts described above for C2-C5 alkynyls and C2-C6 alkynyls, but also C7, C8, C9, and C 10 This also includes alkynyl. Similarly, C2-C 12 Alkinyl includes all of the aforementioned parts, but C 11 and C 12 Includes alkynyl. C2-C 12 Non-limiting examples of alkenyls include ethynyl, propynyl, butynyl, and pentynyl. Unless otherwise specified herein, the alkynyl group may be optionally substituted.

[0049] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain radical having 2 to 12 carbon atoms and one or more carbon-carbon triple bonds. C2-C 12Non-limiting examples of alkylenes include ethynylene and propargylene. The alkylene chain is bonded to the rest of the molecule via single bonds and to radical groups via single bonds. The connection points of the alkylene chain to the rest of the molecule and radical groups can be via one carbon or any two carbons within the chain. Unless otherwise specified herein, alkylene chains may be optionally substituted.

[0050] "alkoxy" is the formula -OR a It refers to the radical of, in the formula, R a This is an alkyl, alkenyl, or alkynyl radical as defined above, containing 1 to 12 carbon atoms. Unless otherwise specified herein, the alkoxy group may be optionally substituted.

[0051] "Alkylamino" is formula -NHR a or -NR a R a It refers to the radical of each R a These are, independently, alkyl, alkenyl, or alkynyl radicals as defined above, containing 1 to 12 carbon atoms. Unless otherwise specified herein, the alkylamino groups may be optionally substituted.

[0052] "Aryl" refers to a hydrocarbon ring radical comprising hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. For the purposes of the present invention, aryl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused ring systems, spirocyclic systems, or bridging ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from acetantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluorantene, fluorene, as-indacene, s-indacene, indan, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specified herein, the term "aryl" means that aryl radicals may be optionally substituted.

[0053] "Aralkyl" or "arylalkyl" is a compound of the formula -R b -R c It refers to the radical of, in the formula, R b R is an alkylene group as defined above, c This is one or more aryl radicals as defined above, such as benzyl, diphenylmethyl, etc. Unless otherwise specified herein, the aralkyl group may be optionally substituted.

[0054] "Carbocyclyl," "carbocyclic ring," or "carbocycle" refers to a non-aromatic, saturated, or unsaturated ring structure in which each atom forming the ring is carbon. A carbocyclic ring can contain 3 to 20 carbon atoms. Carbocyclic rings include cycloalkyl, cycloalkenyl, and cycloalkynyl as defined herein. Unless otherwise specified herein, the carbocyclyl group may be optionally substituted.

[0055] "Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting only of carbon and hydrogen atoms, which may include fused ring systems, spirocyclic systems, or bridging ring systems, having 3 to 20 carbon atoms, for example, having 3 to 10 carbon atoms bonded to the rest of the molecule by single bonds. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, dekalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unless otherwise specified herein, cycloalkyl groups may be optionally substituted.

[0056] A "polycyclic" ring system refers to a ring system containing two or more rings, for example, two, three, or four rings. Polycyclic rings may be fused ring systems, spiro ring systems, or bridging ring systems.

[0057] A "polycyclic cycloalkylene" refers to a divalent, non-aromatic polycyclic, fully saturated hydrocarbon ring consisting only of carbon and hydrogen atoms, having 4 to 20 carbon atoms, for example, 4 to 10 carbon atoms, bonded to the rest of the molecule by two single bonds (as shown in formula I). ​​Polycyclic cycloalkylenes can include fused ring systems, spiro-ring systems, or bridging ring systems. Examples of polycyclic cycloalkylenes include bicyclo[2.2.2]octanylene, cubanylene, bicyclo(1.1.1)pentylene, adamantylene, norbornylene, decalinylene, and 7,7-dimethyl-bicyclo[2.2.1]heptanylene. Unless otherwise specified herein, cycloalkylene groups may be optionally substituted.

[0058] "Haloalkyl" refers to an alkyl radical as defined above, which is substituted by one or more halo radicals as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless otherwise specified herein, haloalkyls may be optionally substituted.

[0059] "Haloalkenyl" refers to an alkenyl radical as defined above, which is substituted with one or more halo radicals as defined above, such as 1-fluoropropenyl, 1,1-difluorobutenyl, etc. Unless otherwise specified herein, the haloalkenyl group may be optionally substituted.

[0060] "Haloalkynyl" refers to an alkynyl radical as defined above, which is substituted by one or more halo radicals as defined above, such as 1-fluoropropynyl, 1-fluorobutynyl, etc. Unless otherwise specified herein, the haloalkynyl group may be optionally substituted.

[0061] "Heterocyclyl," "heterocyclic ring," or "heterocycle" refers to a 3-20 membered non-aromatic, saturated, or unsaturated radical consisting of 2-12 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen, or sulfur. Unless otherwise specified herein, heterocyclyl radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, including fused, spirocyclic, or bridging ring systems; the nitrogen, carbon, or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or completely saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanil, thienyl[1,3]dithianil, decahydroisoquinolyl, imidazolinil, imidazolidinil, isothiazolidinil, isoxazolidinil, morpholinil, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinil, 2-oxopiperidinil, 2-oxopyrrolidinil, oxazolidinil, piperidinil, piperazinil, 4-piperidonyl, pyrrolidinil, pyrazolidinil, quinuclidinil, thiazolidinil, tetrahydrofuryl, trithianil, tetrahydropyranil, thiomorpholinil, thiamorpholinil, 1-oxo-thiomorpholinil, and 1,1-dioxo-thiomorpholinil. Unless otherwise specified herein, heterocyclyl groups may be optionally substituted.

[0062] "Heterocyclylalkyl" is a compound of formulas -R b -R e It refers to the radical of, in the formula, R b R is an alkylene group as defined above, e is a heterocyclyl radical as defined above. Unless otherwise specified herein, heterocycloalkyl groups may be optionally substituted.

[0063] "N-heterocyclyl" refers to a heterocyclyl radical as defined above, which contains at least one nitrogen atom and whose binding site to the rest of the heterocyclyl radical molecule is via the nitrogen atom in the heterocyclyl radical. Unless otherwise specified herein, the N-heterocyclyl group may be optionally substituted.

[0064] A "heteroaryl" refers to a 5-20 membered cyclic radical containing a hydrogen atom, 1-13 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen, and sulfur, and at least one aromatic ring. Heteroaryl radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic systems, including fused or bridging ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized, and the nitrogen atom may be optionally quaternized. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranil, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzothienyl (benzothiophene), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinil, dibenzofuranil, dibenzothiophene, furanil, furanonil, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindri Examples include, but are not limited to, indolinyl, isoindolinyl, isoquinolyl, indolidinyl, isoxazolyl, naphthilidinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxyranil, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyradinyl, 1-oxidepyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thienyl. Unless otherwise specified herein, heteroaryl groups may be optionally substituted.

[0065] "Heteroarylene" refers to a divalent 5-20 membered cyclic radical comprising a hydrogen atom, 1-13 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen, and sulfur, and at least one aromatic ring containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. For the purposes of this disclosure, heteroarylene radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic systems, which may include fused or bridging cyclic systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized, and the nitrogen atom may be optionally quaternized.Examples include azepinylene, acridinylene, benzimidazoylene, benzothiazoylene, benzindoylene, benzodioxorylene, benzofuranylene, benzoxazolylene, benzothiazoylene, benzothiadiazoylene, benzo[b][1,4]dioxepinylene, 1,4-benzodioxanylene, benzonaphthofurane, benzoxazolylene, benzodioxorylene, benzodioxynylene, benzopyranile Benzopyranonirene, benzofuranirene, benzofuranirene, benzothienirene (divalent benzothiophene radical), benzotriazolylene, benzo[4,6]imidazo[1,2-a]pyridinylene, carbazolylen, sinnorinylene, dibenzofuranirene, dibenzothiophene, furanirene, furanorylene, isothiazolylene, imidazolylen, indazolylene, indazolylene, indazolylene, isoindolylene, Drinylene, Isoindrinylene, Isoquinorylene, Indolidinerene, Isoxazolylene, Naphthyridinylene, Oxadiazoylene, 2-Oxoazepinylene, Oxazolylene, Oxyranylene, 1-Oxidopyridinylene, 1-Oxidopyrimidinylene, 1-Oxidopyridinerene, 1-Oxidopyridadinylene, 1-Phenyl-1H-pyrroleylene, Phenadinylene, Phenothiazinylene, Phenoxadinylene, Phthalazine Examples include, but are not limited to, lene, pteridinylene, prinylene, pyrrolylene, pyrazolylene, pyridinylene, pyridinylene, pyrimidinylene, pyridadinylene, quinazolinylene, quinoxalinylene, quinolinylene, quinuclidinylene, isoquinolinylene, tetrahydroquinolinylene, thiazolylen, thiadiazolylen, triazolylene, tetrazolylen, triazinylene, and thiophene (e.g., thienylene). Unless otherwise specified herein, heteroarylene groups may be optionally substituted.

[0066] "N-heteroaryl" refers to a heteroaryl radical as defined above, which contains at least one nitrogen atom and whose bonding site to the rest of the molecule is via the nitrogen atom in the heteroaryl radical. Unless otherwise specified herein, the N-heteroaryl group may be optionally substituted.

[0067] "Heteroarylalkyl" is a compound of the formula -R b -R f It refers to the radical of, in the formula, R b R is an alkylene chain as defined above, f is a heteroaryl radical as defined above. Unless otherwise specified herein, heteroarylalkyl groups may be optionally substituted.

[0068] "Thioalkyl" is represented by formula -SR a It refers to the radical of, in the formula, R a This is an alkyl, alkenyl, or alkynyl radical as defined above, containing 1 to 12 carbon atoms. Unless otherwise specified herein, thioalkyl groups may be optionally substituted.

[0069] As used herein, the term “substitution” means any of the above groups (e.g., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, carbocyryl, cycloalkyl, cycloalkylene, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl), wherein at least one hydrogen atom is a halogen atom such as F, Cl, Br, and I; These include, but are not limited to, oxygen atoms of groups such as droxyl groups, alkoxy groups, and ester groups; sulfur atoms of groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfon groups; nitrogen atoms of groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; silicon atoms of groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups, as well as other heteroatoms of various other groups, which can be replaced by bonding to non-hydrogen atoms.

[0070] "Substitution" also means any of the above groups in which one or more hydrogen atoms are replaced by a heteroatom, such as oxygen in oxo, carbonyl, carboxyl, and ester groups, as well as by a higher-order bond (e.g., a double or triple bond) to the nitrogen of groups such as imines, oximes, hydrazones, and nitriles. For example, "substitution" means that one or more hydrogen atoms are replaced by -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g SO2R h -OC(=O)NR g R h , -OR g , -SR g -SOR g , -SO2R g , -OSO2R g , -SO2OR g ,=NSO2R g , and -SO2NR g R h Includes any of the above groups that are replaced by -C(=O)R. "Substitution" also means that one or more hydrogen atoms are replaced by -C(=O)R g , -C(=O)OR g -C(=O)NR g R h -CH2SO2R g -CH2SO2NR g R h It means any of the above bases that are replaced by R. g and R h"Substitution" is the same or different and independently of any of the above groups, which are hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. In addition, each of the aforementioned substituents may be optionally substituted with one or more of the substituents mentioned above.

[0071] Where used herein, the symbol [ka] A (hereinafter referred to as a "bond point bond") represents a bond between two chemical substances, where one substance is shown as being bonded to the bond point bond, and the other is not shown as being bonded to the bond point bond. For example, [ka] This indicates that chemical substance "XY" is bonded to another chemical substance via bond-point bonding. Furthermore, specific bond points to unshown chemical substances can be identified by inference. For example, compound CH3-R L (In the formula, R L H or [ka] (is) R L If it is "XY", then the bond point connection is R L It is inferred that this is the same bond shown as the bond attached to CH3.

[0072] In this specification, unless otherwise specified, the term “pharmaceutically acceptable” is used to characterize a part (e.g., a salt, dosage form, or excipient) as appropriate for use in accordance with sound medical judgment. Generally, a pharmaceutically acceptable part has one or more benefits that outweigh any adverse effects it may have. Adverse effects may include, for example, excessive toxicity, irritation, allergic reactions, and other problems and complications.

[0073] "Pharmacologically acceptable salts" include both acid addition salts and base addition salts. Examples of pharmaceutically acceptable salts include those obtained by reacting an active compound that functions as a base with an inorganic or organic acid to form salts, such as salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonate. Those skilled in the art will further recognize that acid addition salts can be prepared by reacting a compound with a suitable inorganic or organic acid via one of several known methods.

[0074] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined with respect to an amino acid as (R)- or (S)- or (D)- or (L)- from an absolute stereochemical standpoint. This disclosure is intended to include all such possible isomers, whether or not they are specifically shown herein, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or can be decomposed using prior art, e.g., chromatography and fractionation crystallization. Prior art for preparing / isolating individual enantiomers includes chiral synthesis from suitable optically pure precursors, or, for example, the decomposition of racemates (or racemates of salts or derivatives) using chiral high-pressure liquid chromatography (HPLC). Where a compound described herein contains an olefin double bond or other geometrically asymmetric center, unless otherwise specified, the compound is intended to include both E and Z geometric isomers. Similarly, all tautomer forms are also intended to be included.

[0075] A "stereoisomer" refers to a compound that consists of the same atoms bonded together by the same bonds, but has different three-dimensional structures that are not interchangeable. This disclosure intends various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers that are mirror images of each other but whose molecules cannot be superimposed.

[0076] As used herein with respect to a patient, the term “to treat” means to improve at least one symptom of the patient’s disorder. Treatment may be to improve, or at least partially improve, the disorder or symptoms associated with the disorder.

[0077] "Effective dose" means a quantity of a compound or pharmaceutical preparation sufficient to perform a treatment when administered to a patient for the purpose of treating a condition, disorder, or disease.

[0078] The term “therapeutically effective” as applied to dosage or quantity refers to the amount of compound or pharmaceutical preparation sufficient to produce the desired clinical benefit after administration to a patient who needs it. “Therapeutic effective dose” refers, in some embodiments, to the dosage or quantity of compound or pharmaceutical preparation sufficient to produce prevention after administration to a patient who needs prevention.

[0079] The terms “subject,” “individual,” and “patient” are used interchangeably herein to refer to vertebrates such as mammals. Mammals may be, for example, mice, rats, rabbits, cats, dogs, pigs, sheep, horses, non-human primates (e.g., crab-eating macaques, chimpanzees), or humans.

[0080] compound In various embodiments, the Disclosure provides DPP1 inhibitors of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or the DPP1 inhibitors listed in Table 1.

[0081] formula In some embodiments, the present disclosure relates to a compound of formula (I), [ka] (I) or a pharmaceutically acceptable salt or deuterated form thereof is provided.

[0082] In embodiments, the present disclosure relates to a compound of formula (II), [ka] (II) or a pharmaceutically acceptable salt or deuterated form thereof is provided.

[0083] This disclosure relates to a compound of formula (III), [ka] (III) or a pharmaceutically acceptable salt or deuterated form thereof, wherein the formula,

[0084] In embodiments, the present disclosure relates to a compound of formula (IV), [ka] (IV) or a pharmaceutically acceptable salt or deuterated form thereof, wherein the formula,

[0085] In embodiments, the present disclosure relates to a compound of formula (V), [ka] (V) or a pharmaceutically acceptable salt or deuterated form thereof is provided.

[0086] In embodiments, the present disclosure relates to a compound of formula (VI), [ka] (VI) or a pharmaceutically acceptable salt or deuterated form thereof is provided.

[0087] In embodiments, the present disclosure relates to a compound of formula (VII), [ka] (VII) or a pharmaceutically acceptable salt or deuterated form thereof is provided.

[0088] In embodiments, the present disclosure relates to a compound of formula (XIV), [ka] , The present invention provides a pharmaceutically acceptable salt or deuterated form thereof.

[0089] In embodiments, the present disclosure relates to a compound of formula (VIII), [ka] (VIII) or a pharmaceutically acceptable salt or deuterated form thereof is provided.

[0090] In embodiments, the present disclosure relates to a compound of formula (IX), [ka] (IX) or a pharmaceutically acceptable salt or deuterated form thereof is provided.

[0091] In embodiments, the present disclosure relates to a compound of formula (X), [ka] (X), or a pharmaceutically acceptable salt or deuterated form thereof, is provided.

[0092] In embodiments, the present disclosure relates to a compound of formula (XI), [ka] (XI) or a pharmaceutically acceptable salt or deuterated form thereof is provided.

[0093] In embodiments, the present disclosure relates to a compound of formula (XII), [ka] (XII), or a pharmaceutically acceptable salt or deuterated form thereof, is provided.

[0094] In embodiments, the present disclosure relates to a compound of formula (XIII), [ka] (XIII) or a pharmaceutically acceptable salt or deuterated form thereof is provided.

[0095] In embodiments, the present disclosure relates to a compound of formula (XV), [ka] The present invention provides a pharmaceutically acceptable salt or deuterated form thereof.

[0096] In embodiments, the present disclosure relates to a compound of formula (XVI), [ka] (XVI) or a pharmaceutically acceptable salt or deuterated form thereof is provided.

[0097] In embodiments, the present disclosure relates to a compound of formula (XVII), [ka] (XVII), or a pharmaceutically acceptable salt or deuterated form thereof is provided.

[0098] In embodiments, this disclosure relates to a compound of formula (XVIII), [ka] (XVIII), or a pharmaceutically acceptable salt or deuterated form thereof is provided.

[0099] In embodiments, this disclosure relates to a compound of formula (XIX), [ka] The present invention provides a pharmaceutically acceptable salt or deuterated form thereof.

[0100] In embodiments, the present disclosure relates to a compound of formula (XX), [ka] The present invention provides a pharmaceutically acceptable salt or deuterated form thereof.

[0101] R in formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX) 0 , L, R 1 , R 6 , R 7 , R 8 , R g , R 10 n, X, X′, X 1 , X 2 , X 3 , X 4 , R A , R B Rings B, C, D, E, and F are described herein.

[0102] R 0 In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 It is a 5-12 member monocyclic heterocyclyl containing 1-3 heteroatoms selected from N, S, and O, and the monocyclic heterocycle contains 1-3 R 8 The polycyclic heterocycline is optionally substituted with a group and contains 1 to 3 heteroatoms selected from N, S, and O, and the polycyclic heterocycle contains 1 to 3 R 8 It is optionally substituted at the base. In the embodiment, each R 8 These are independently H, halogen, oxo, cyano, hydroxyl, NH2, and NH(C) 1-6 Alkyl), N(C 1-6 Alkyl)2, COOH, C 1-6 Alkyl, C 1-6 Alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6Alkoxy, C halogenated 1-6 Alkoxy, C 1-6 Alkilen-carbocykrill, or C 1-6 Selected from alkylene-heteroaryls.

[0103] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, each R 8 These are independently H, halogen, oxo, cyano, hydroxyl, NH2, and NH(C) 1-6 Alkyl), N(C 1-6 Alkyl)2, COOH, C 1-6 Alkyl, C 1-6 Alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6 Alkoxy, C halogenated 1-6 Alkoxy, C 1-6 Alkilen-carbocykrill, or C 1-6 Selected from alkylene-heteroaryls.

[0104] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 8 These are H, OH, halogen, NH2, COOH, C1-6 alkyl, C1-6 alkyl-OH, C1-6 alkoxy, or halogenated C1-6 alkoxy.

[0105] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 8 These are H, OH, halogen, NH2, COOH, unsubstituted C1-6 alkyl, C1-6 alkyl-OH, unsubstituted C1-6 alkoxy, or halogenated C1-6 alkoxy.

[0106] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 8 is hydrogen, methoxy, or hydroxyl.

[0107] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 8 It is methoxy.

[0108] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 8 It is OH.

[0109] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 8 It is hydrogen.

[0110] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 It is a 5-12 member monocyclic heterocyclyl containing 1-3 heteroatoms selected from N, S, and O, and the monocyclic heterocycle contains 1-3 R 8 The group is optionally substituted. In embodiments of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 but, [ka] And in the formula, X1 and X2 independently determine O, S, NH, N(C) 1-6 Alkyl, or CR 12 R 13 And at least one of X1 and X2 is CR 12 R 13 Instead, X3 is O, S, NH, or N(C 1-6 It is alkyl, R 8 However, H, halogen, oxo, cyano, hydroxyl, NH2, NH(C 1-6Alkyl), N(C 1-6 Alkyl)2, COOH, C 1-6 Alkyl, C 1-6 Alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6 Alkoxy or halogenated C 1-6 It is an alkoxy, R 12 However, H, halogen, cyano, hydroxyl, NH2, NH(C 1-6 Alkyl), N(C 1-6 Alkyl)2, COOH, C 1-6 Alkyl, C 1-6 Alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6 Alkoxy or halogenated C 1-6 It is an alkoxy, R 13 However, independently, these are H, halogen, or C1-C6 alkyl. R A However, H, C 1-6 Alkyl, C 1-6 Alkilen-carbocykrill, or C 1-6 It is an alkylene-heteroaryl, R B However, C 1-6 Alkyl, C 2-6 Alkenil, C 1-6 Alkilen-carbocykrill, or C 1-6 It is either an alkylene heteroaryl or R A and R B However, they come together to form a heterocycline, m is 0, 1, 2, or 3.

[0111] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 13is independently H, F, Cl, Br, I, or C1-C6 alkyl. In embodiments, R 13 is independently H, F, or C1-C6 alkyl. In embodiments, R 13 H is H.

[0112] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 12 These are H, OH, halogen, NH2, COOH, unsubstituted C1-4 alkyl, C1-4 alkyl-OH, unsubstituted C1-4 alkoxy, or halogenated C1-4 alkoxy.

[0113] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 12 It is hydrogen.

[0114] In embodiments of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), or (XVI), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, X is O, S, CHF, or CF2.

[0115] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, X is O, S, or CF2.

[0116] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, X is O.

[0117] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, X is S.

[0118] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, X is CF2.

[0119] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, X1 and X2 are independently O, S, NH, N(C) 1-6 Alkyl, or CR 12 R 13 And at least one of X1 and X2 is CR 12 R 13 No. In the embodiment, at least X1 is O, S, NH, N(C 1-6 It is alkyl.

[0120] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, X1 and X2 are independently O, S, NH, N(C) 1-6 It is alkyl.

[0121] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, X1 and X2 are independently O or NH.

[0122] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, X3 is O, S, NH, or N(C) 1-6 It is alkyl.

[0123] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, X3 is O, S, or NH.

[0124] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, X3 is O.

[0125] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 teeth, [ka] That is the case.

[0126] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R A H, C 1-6 Alkyl, C 1-6 Alkilen-carbocykrill, or C 1-6 It is an alkylene-heteroaryl compound.

[0127] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R A H, C 1-6 Alkyl, C 1-6 Alkilen-carbocykrill, or C 1-6 It is an alkylene-heteroaryl, R B C 1-6 Alkyl, C 2-6 Alkenil, C 1-6 Alkilen-carbocykrill, or C 1-6 It is either an alkylene heteroaryl or R A and R B They combine to form heterocyclines.

[0128] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R A is H or C 1-6It is alkyl.

[0129] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R A H is H.

[0130] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R A C 1-6 It is alkyl.

[0131] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R A It is -CH3.

[0132] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R B C 1-6 Alkyl, C 2-6 Alkenil, C 1-6 Alkilen-carbocykrill, or C 1-6 It is an alkylene-heteroaryl compound.

[0133] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R B C 1-6 Alkyl, C 2-6 Alkenil, C 1-6 Alkilen-carbocykrill, or C 1-6 It is an alkylene-heteroaryl compound.

[0134] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R B C 1-6 Alkyl, C 1-6 Alkylene-aryl, or -C 1-6 It is an alkylene-5 to 6-membered heteroaryl.

[0135] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R B C 1-6 It is alkyl.

[0136] In embodiments of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), R A and R B They combine to form heterocyclines.

[0137] Another embodiment is a product obtainable by any of the processes or examples disclosed herein.

[0138] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 teeth, [ka] That is the case.

[0139] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 teeth, [ka] In this embodiment, m is 2 or 3.

[0140] In the embodiment, m is 2. In the embodiment of the compound, R 0 teeth, [ka] That is the case.

[0141] In this embodiment, R 0 teeth, [ka] In the formula, X1 is O, X2 is NH, and R 8 C 1-6 It is an alkoxy.

[0142] In this embodiment, R 0 teeth, [ka] That is the case.

[0143] In this embodiment, R 0 teeth, [ka] That is the case.

[0144] In this embodiment, R 0 teeth, [ka] That is the case.

[0145] In this embodiment, R 0 teeth, [ka] That is the case.

[0146] Compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or in one embodiment of their deuterated forms, R 0 teeth, [ka] That is the case.

[0147] In this embodiment, R 0 teeth, [ka] That is the case.

[0148] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 teeth, [ka] That is the case.

[0149] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 teeth, [ka] And in the formula, each R 8 These are H, halogen, and C, independently. 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Selected from alkoxy.

[0150] In this embodiment, R 0 teeth, [ka] That is the case.

[0151] In this embodiment, R 0 teeth, [ka] That is the case.

[0152] In this embodiment, R 0 teeth, [ka] That is the case.

[0153] In this embodiment, R 0 teeth, [ka] That is the case.

[0154] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 teeth, [ka] That is the case.

[0155] In this embodiment, R 0 teeth, [ka] That is the case.

[0156] In this embodiment, R 0 teeth, [ka] That is the case.

[0157] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 teeth, [ka] That is the case.

[0158] In this embodiment, R 0 teeth, [ka] That is the case.

[0159] In this embodiment, R 0 teeth, [ka] That is the case.

[0160] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 teeth, [ka] That is the case.

[0161] In this embodiment, R 0 teeth, [ka] That is the case.

[0162] In this embodiment, R 0 teeth, [ka] That is the case.

[0163] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 teeth, [ka] That is the case.

[0164] In this embodiment, R 0 teeth, [ka] That is the case.

[0165] In this embodiment, R 0 teeth, [ka] That is the case.

[0166] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 teeth, [ka] That is the case.

[0167] In this embodiment, R 0 teeth, [ka] That is the case.

[0168] In this embodiment, R 0 teeth, [ka] That is the case.

[0169] In this embodiment, R 0 teeth, [ka] That is the case.

[0170] In this embodiment, R 0 teeth, [ka] That is the case.

[0171] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 teeth, [ka] That is the case.

[0172] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 teeth, [ka] The conditions are such that each n1, n2, and n3 is an integer between 0 and 3 independently, the sum of n1, n2, and n3 is less than or equal to 4, and X1 and X2 are independently O, S, NR 6 , or CR 12 R 13 And at least one of X1 and X2 is CR 12 R 13 Rather, each R 6 , R 12 , and R 13 However, independently, these are H, halo, or C1-C6 alkyl. In embodiments of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 teeth, [ka] And R 8 These are H, F, OH, CH3, OCH3, OCHF2, OCF3, OCH2CH3, or -CH2OCH3.

[0173] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 teeth, [ka] That is the case.

[0174] In this embodiment, R 0 teeth, [ka] That is the case.

[0175] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 A polycyclic heterocycle is a 5-12 membered polycyclic heterocycle containing 1-3 heteroatoms selected from N, S, and O, and a polycyclic heterocycle contains 1-3 R 8 It is optionally substituted with. In embodiments of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or their pharmaceutically acceptable salts, or their deuterated forms, the 5-12 membered polycyclic heterocycle is (i) A 5-12 membered spiroheterocycle containing 1-3 heteroatoms selected from N, S, and O, wherein the spiroheterocycle contains 1-3 R 8 A 5-12 member spirohetall ring, which is optionally substituted by (ii) A 5-12 membered fused heterocycle containing 1-3 heteroatoms selected from N, S, and O, wherein the fused heterocycle contains 1-3 R 8 A 5- to 12-membered condensed heterocycle, which is optionally substituted by, (iii) A 7-12 membered bridging heterocycle containing 1-3 heteroatoms selected from N, S, and O, wherein the bridging heterocycle contains 1-3 R 8 It is a 7- to 12-membered bridged heterocycle that is optionally substituted.

[0176] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 A spiroheterocycle is a 5-12 membered spiroheterocycle containing 1-3 heteroatoms selected from N, S, and O, and the spiroheterocycle contains 1-3 R 8 It is being replaced by an arbitrary choice.

[0177] In this embodiment, the 5-12 member spiroheterocyclic ring is [ka] Thereafter, m1 and m2 are independently 0, 1, or 2, provided that neither m1 nor m2 is 0, nor neither m1 nor m2 is 2, and p is 1 or 2.

[0178] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 It is a 5-12 membered fused heterocycle containing 1-3 heteroatoms selected from N, S, and O, and the fused heterocycle contains 1-3 R 8 It is being replaced by an arbitrary choice.

[0179] In this embodiment, the 5- to 12-membered condensed heterocycle is [ka] And, m4 is 0 or 1, m5 is either 1 or 2. X 2 However, O, S, NH, N(C1-6 Alkyl, or CR 12 R 13 And, R 12 However, H, halogen, cyano, hydroxyl, NH2, NH(C 1-6 Alkyl), N(C 1-6 Alkyl)2, COOH, C 1-6 Alkyl, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6 Alkoxy or halogenated C 1-6 Selected from alkoxy, R 13 However, they are independently H, F, Cl, Br, I, or C1-C6 alkyl.

[0180] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, [ka] teeth, [ka] That is the case.

[0181] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 teeth, [ka] And in the formula, X2 is O, S, NH, N(C 1-6 Alkyl, or CR12 R 13 And, R 12 However, H, halogen, cyano, hydroxyl, NH2, NH(C 1-6 Alkyl), N(C 1-6 Alkyl)2, COOH, C 1-6 Alkyl, -CONH2, -S(=O)NH2, -S(O)2NH2, C 1-6 Alkoxy or halogenated C 1-6 It is an alkoxy, R 13 However, it is H, halogen, or C1-C6 alkyl, Each m and m' is an independent integer between 0 and 3, and the sum of m and m' is 3 or less.

[0182] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 teeth, [ka] That is the case.

[0183] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 teeth, [ka] And in the formula, X 2 It is NH, O, or S.

[0184] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 teeth, [ka] That is the case.

[0185] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 teeth, [ka] That is the case.

[0186] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 teeth, [ka] That is the case.

[0187] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 teeth, [ka] That is the case.

[0188] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 It is a 7-12 membered bridging heterocycle containing 1-3 heteroatoms selected from N, S, and O, and the bridging heterocycle contains 1-3 R 8 It is being replaced by an arbitrary choice.

[0189] In the embodiment, the 7-12 membered bridged heterocycle is [ka] And each of these has 1 to 4 R 8 It is optionally replaced by, A is a bond, -O-, -O-CH2-, -CH2-O-CH2-, -CH2OCH2CH2-, -CH2-, -CH2CH2-, or -CH2NH-, B is N or CH, m4 is 0 or 1, p1 is 0, 1, or 2, q1 is 1, 2, or 3.

[0190] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 teeth, [ka] That is the case.

[0191] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 0 teeth, [ka] Selected from.

[0192] L In embodiments of the compound of formula (I), its pharmaceutically acceptable salt, or its deuterated form, L is a polycyclic cycloalkylene, a polycyclic arylene, or a polycyclic heteroarylene.

[0193] In the embodiment, the polycyclic cycloalkylene is formed at the first quaternary carbon of the polycyclic cycloalkylene. 1 It is connected to and via the second quaternary carbon of the polycyclic cycloalkylene. [ka] It is connected independently.

[0194] In the embodiment, the first atom of the first ring of the polycyclic arylene or polycyclic heteroarylene is [ka] The second atom of the second ring of the polycyclic arylene or heteroarylene is connected to R 1 It connects to the network.

[0195] In this embodiment, L is independently 0 to 4 R 10 It is replaced by.

[0196] Control mechanism, each R 10 However, independently, =O, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, SC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1-6 Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CON 1-6 Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6 The molecule is alkyl or heterocyclic, and each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic molecule is independently and optionally substituted with 1 to 3 substituents selected from halogens, cyano, hydroxyl, NH2, and COOH.

[0197] In this embodiment, L is a polycyclic cycloalkylene.

[0198] In this embodiment, the polycyclic cycloalkylene contains 4 to 10 carbon atoms.

[0199] In the embodiment, the polycyclic cycloalkylene is formed at the first quaternary carbon of the polycyclic cycloalkylene. 1 It is connected to and via the second quaternary carbon of the polycyclic cycloalkylene. [ka] It is connected independently.

[0200] In embodiments of the compound of formula (I), its pharmaceutically acceptable salt, or its deuterated form, L is [ka] That is the case.

[0201] In further embodiments, L is [ka] That is the case.

[0202] In this embodiment, L is [ka] That is the case.

[0203] In this embodiment, L is [ka] That is the case.

[0204] In this embodiment, L is [ka] That is the case.

[0205] In embodiments of the compound of formula (I), its pharmaceutically acceptable salt, or its deuterated form, L is 0 to 4 R 10 It is a polycyclic heteroarylene substituted by. In embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a deuterated form thereof, L is a polycyclic heteroarylene containing 8 to 12 ring atoms and 0 to 4 R 10 It is substituted by. In embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a deuterated form thereof, L is a polycyclic heteroarylene containing 9 to 10 ring atoms, and 0 to 4 R 10It is substituted by. In embodiments of the compound of formula (I), or its pharmaceutically acceptable salt or deuterated form, the polycyclic heteroarylene contains 8 to 10 ring atoms and 0 to 4 R 10 It is substituted by. In embodiments of the compound of formula (I), or its pharmaceutically acceptable salt or deuterated form, the polycyclic heteroarylene contains 8 to 9 ring atoms and 0 to 4 R 10 It is substituted by. In embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a deuterated form thereof, L is a polycyclic heteroarylene comprising nine ring atoms selected from O, N, or S and one or two heteroatoms, the polycyclic heteroarylene having 0 to 4 R 10 It is substituted by. In embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a deuterated form thereof, L is a polycyclic heteroarylene comprising eight ring atoms selected from O, N, or S and 1 to 3 heteroatoms, the polycyclic heteroarylene having 0 to 4 R 10 It is substituted by. In embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a deuterated form thereof, L is 0 R 10 It is a polycyclic heteroarylene substituted by. In embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a deuterated form thereof, L is one R 10 It is a polycyclic heteroarylene substituted by [substance name].

[0206] In embodiments of the compound of formula (I), or its pharmaceutically acceptable salt or deuterated form, L is 0 to 4 R 10 Replaced by [ka] And ring B is a heteroaryl ring. If L is a polycyclic heteroarylene, then the polycyclic heteroarylene can be any orientation (for example, [ka] ) may have.

[0207] In embodiments of the compound of formula (I), its pharmaceutically acceptable salt, or its deuterated form, the polycyclic heteroarylene contains 0 to 4 R 10 Replaced by [ka] In the formula, X' is O, S, NH, or N(C 1-6 In embodiments of the compound of formula (I), or its pharmaceutically acceptable salt, or its deuterated form, the polycyclic heteroarylene has 0 to 4 R 10 These are benzothienylene, indolylene, or benzofuranylene, substituted by the following:

[0208] In embodiments of the compound of formula (I), its pharmaceutically acceptable salt, or its deuterated form, the polycyclic heteroarylene is [ka] Each of these has 0 to 4 R 10 It has been replaced by.

[0209] In embodiments of the compound of formula (I), its pharmaceutically acceptable salt, or its deuterated form, the polycyclic heteroarylene contains 0 to 4 R 10 Replaced by [ka] That is the case.

[0210] In embodiments of the compound of formula (I), its pharmaceutically acceptable salt, or its deuterated form, the polycyclic heteroarylene contains 0 to 4 R 10 Replaced by [ka] That is the case.

[0211] In embodiments of the compound of formula (I), its pharmaceutically acceptable salt, or its deuterated form, L is 0 to 4 R 10 This is benzothienylene substituted with [another compound].

[0212] In this embodiment, L is 0 to 4 R 10 Replaced by [ka] That is the case.

[0213] In this embodiment, L is [ka] That is the case.

[0214] In embodiments of the compound of formula (I), its pharmaceutically acceptable salt, or its deuterated form, [ka] teeth, [ka] Bonded to the phenyl ring, R 1 teeth, [ka] Bonded to a 5-membered ring, in the formula, [ka] This is 0 to 4 R 10 It has been replaced by.

[0215] In embodiments of the compound of formula (I), or its pharmaceutically acceptable salt or deuterated form, [ka] teeth, [ka] Bonded to the 5-membered ring, R 1 teeth, [ka] Bonded to the phenyl ring, in the formula, [ka] This is 0 to 4 R 10 It has been replaced by.

[0216] In embodiments of the compound of formula (I), or its pharmaceutically acceptable salt or deuterated form, the polycyclic heteroarylene is [ka] That is the case.

[0217] In embodiments of the compound of formula (I), or its pharmaceutically acceptable salt or deuterated form, L is 1 to 4 R 10 Replaced by [ka] That is the case.

[0218] In embodiments of the compound of formula (I), or its pharmaceutically acceptable salt or deuterated form, L is one R 10 Replaced by [ka] That is the case.

[0219] In embodiments of the compound of formula (I), or its pharmaceutically acceptable salt or deuterated form, R 10 It is a halo.

[0220] In embodiments of the compound of formula (I), or its pharmaceutically acceptable salt or deuterated form, L is [ka] That is the case.

[0221] In embodiments of the compound of formula (I), or its pharmaceutically acceptable salt or deuterated form, L is a polycyclic heteroarylene comprising eight ring atoms selected from O, N, or S and one or two heteroatoms, wherein the polycyclic heteroarylene has 0 to 4 R 10 It is replaced by.

[0222] In embodiments of the compound of formula (I), or its pharmaceutically acceptable salt or deuterated form, L is [ka] That is the case.

[0223] In embodiments of the compound of formula (I) or (XVI), or a pharmaceutically acceptable salt or deuterated form thereof, L is [ka] Each of rings E and F is a five-membered heteroaryl or heterocyclyl containing one to three heteroatoms selected from O, N, or S.

[0224] In embodiments of the compound of formula (I) or (XVI), or a pharmaceutically acceptable salt or deuterated form thereof, L is [ka] Each of rings E and F is a 5-membered heteroaryl containing 1 to 3 heteroatoms selected from O, N, or S.

[0225] In embodiments of the compound of formula (I) or (XVI), or a pharmaceutically acceptable salt or deuterated form thereof, L is [ka] That is the case.

[0226] In embodiments of the compound of formula (I) or (XVI), or a pharmaceutically acceptable salt or deuterated form thereof, L is [ka] That is the case.

[0227] In embodiments of the compound of formula (I), L is a polycyclic arylene.

[0228] In embodiments of the compound of formula (I), L is [ka] That is the case.

[0229] In embodiments of the compound of formula (I), L is [ka] That is the case.

[0230] In embodiments of the compounds of formulas (I), (V), (VI), (VII), (XI), (XII), (XIII), or their pharmaceutically acceptable salts, or their deuterated forms, R 10 These are independently oxo, halogen, and C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1-6 Alkyl, -N(C 1-4 Alkyl)2,-COOH,-COC 1-6 Alkyl, -COOC 1-6 Alkyl, -CON 1-6 Alkyl, -CON(C 1-6 Alkyl)2,-NHCOC 1-6The molecule is alkyl or heterocyclic, and each alkyl, alkynyl, cycloalkyl, and heterocyclic molecule is independently and optionally substituted with 1 to 3 substituents selected from halogens, cyano, hydroxyl, NH2, and -COOH.

[0231] In embodiments of the compounds of formulas (I), (V), (VI), (VII), (XI), (XII), (XIII), or their pharmaceutically acceptable salts, or their deuterated forms, R 10 These are independently oxo, halogen, and C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxy, NH2, -NH-C 1-6 Alkyl, -N(C 1-4 Alkyl)2,-COOH,-COC 1-6 Alkyl, -COOC 1-6 Alkyl, -CON 1-6 Alkyl, -CON(C 1-6 Alkyl)2,-NHCOC 1-6 The molecule is a 4- to 7-membered heterocycle containing alkyl or 1-3 heteroatoms selected from N, S, and O, and each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle is independently optionally substituted with 1-3 substituents selected from halogen, cyano, hydroxyl, NH2, and -COOH.

[0232] In embodiments of the compounds of formulas (I), (V), (VI), (VII), (XI), (XII), (XIII), or their pharmaceutically acceptable salts, or their deuterated forms, R 10 These are, independently, halogen, C 1-4 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, cyano, hydroxy, NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2,-COOH,-COC 1-6Alkyl, -COOC 1-6 Alkyl, -CON 1-6 Alkyl, -CON(C 1-6 Alkyl)2, or -NHCOC 1-6 The alkyl group is alkyl, and each alkyl and alkoxy group is independently and optionally substituted with 1 to 3 substituents selected from halogen, cyano, hydroxyl, NH2, and -COOH groups.

[0233] In embodiments of compounds of formulas (I), (V), (VI), (VII), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 10 It is a halogen.

[0234] In embodiments of compounds of formulas (I), (V), (VI), (VII), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 10 It is fluoro.

[0235] In embodiments of compounds of formulas (I), (V), (VI), (VII), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, n is 0.

[0236] In embodiments of compounds of formulas (I), (V), (VI), (VII), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, n is 1.

[0237] In embodiments of compounds of formulas (I), (V), (VI), (VII), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, n is 2.

[0238] In embodiments of compounds of formulas (I), (V), (VI), (VII), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, n is 1, and R 10 It is fluoro.

[0239] In embodiments of compounds of formulas (I), (V), (VI), (VII), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, n is 1, and R 10 The substituent is L, for example, [ka] It is located on the phenyl ring.

[0240] In embodiments of the compounds of formulas (I), (V), (VI), (VII), (XI), (XII), (XIII), or their pharmaceutically acceptable salts, or their deuterated forms, n is 1, and R 10 The substituent is L, for example, [ka] It is located on the thiophene ring.

[0241] R 1 In embodiments of the compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (XIV), or their pharmaceutically acceptable salts, or their deuterated forms, R 1 (i) 1 to 3 Rg (ii) 5-12 member carbocyclyls optionally substituted, (ii) 1-3 R g A 5-12 member monocyclic heterocyclil containing 1-3 heteroatoms selected from (iii)N, S, or O, which are optionally substituted with 6-18 member aryl, wherein the monocyclic heterocyclil contains 1-3 R g A 5-12 member monocyclic heterocycline, which is optionally substituted with (iv)N, S, or O, and a 5-12 member monocyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heteroaryl contains 1-3 R g A 7-14 member bicyclic heteroaryl containing a 5-12 member monocyclic heteroaryl, selected from (v)N, S, or O, which is optionally substituted, wherein the bicyclic heteroaryl contains 1-4 R g A 7-14 member bicyclic heteroaryl, or a 7-20 member tricyclic heteroaryl containing 1-3 heteroatoms selected from (vi)N, S, or O, wherein the tricyclic heteroaryl contains 1-5 R g It is a 7-20 member tricyclic heteroaryl that is optionally substituted with R. In the embodiment, R 1 This is 1 to 3 R g It is a 5-12 member carbocyclyl optionally substituted with R. In the embodiment, R 1 This is 1 to 3 R g It is a 6- to 18-membered aryl that is optionally substituted with R. In the embodiment, R 1 This is a 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, or O, and the monocyclic heterocycline contains 1-3 R g It is optionally replaced by R. In this embodiment, 1 This is a 5-12 member monocyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, and the monocyclic heteroaryl contains 1-3 R g It is optionally replaced by R. In this embodiment, 1This is a 7-14 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, and the bicyclic heteroaryl contains 1-4 R g It is optionally replaced by R. In this embodiment, 1 This is a 7-20 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, and the tricyclic heteroaryl contains 1-5 R g It is optionally replaced by R. In this embodiment, each R g These are independently hydrogen, SF5, =O, halogen, cyano, hydroxyl, nitro, NH2, -COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 2-6 Alkenil, C 2-5 Alkinyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2,-COC 1-6 Alkyl, -COOC 1-6 Alkyl, -CONH2, -CONHC 1-6 Alkyl, -CONHC 3-6 Cycloalkyl, -CON(C 1-6 Alkyl)2,-NHCOC 1-6 Alkyl, -NHCOC 3-5 Cycloalkyl, -P(O)(C 1-6 Alkyl), -S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6 Cycloalkyl, -SO2-3~7 member heterocyclyl, -S(O)NH2, -S(O)NHC 1-6 Alkyl, -S(O)N(C) 1-6 Alkyl)2,-S(O)2NH2,-OSO2-C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8- A 3- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from cycloalkenyloxy, aryl, heteroaryl, N, S, and O, R g However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 -Alkylene-OH, -CONH2,NH2,C 1-6 Further optionally substituted with 1 to 3 groups selected from a 5-7 membered heterocycle containing alkoxy, hydroxyl, -COOH, halogen, or N, S, and O, wherein the 5-7 membered heterocycle is =O, halogen, cyano, C 1-6 Alkyl, and C 1-6 It is optionally substituted with one or two groups selected from haloalkyl groups.

[0242] In embodiments of the compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (XIV), or their pharmaceutically acceptable salts, or their deuterated forms, R g R 6 , R 7 , R 11 , R 14 , or R 15 Selected from, Each R 6 and R 11 However, independently, H, C 1-6 Alkyl, -COC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl and C 3-6 Selected from cycloalkyl groups, alkyl, alkenyl, alkynyl, and cycloalkyl groups are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH. Each R 7 However, independently, H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxyl, NH2, NHC 1-6Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CONHC 1-6 Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6 Selected from alkyl and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, or O, R 7 The alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups within are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH. R 14 and R 15 However, each is independent of H, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, cyano, hydroxyl, NH2, COOH, -S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6 Selected from cycloalkyl groups, -SO2-3 to 7-membered heterocyclines, and 4 to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycles are optionally substituted with 1 to 3 groups selected from halogens, cyano, hydroxyl, NH2, and -COOH. Alternatively, R 14 and R 15 However, it forms =O.

[0243] In embodiments of the compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (XIV), or their pharmaceutically acceptable salts, or their deuterated forms, R 1 This is 1 to 3 R gIt is a 5-12 member carbocyclyl optionally substituted with a group. In the embodiment, R 1 teeth, [ka] Each of these has 1 to 3 R g It is being replaced by an arbitrary choice.

[0244] In embodiments of the compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (XIV), or their pharmaceutically acceptable salts, or their deuterated forms, R 1 This is 1 to 3 R g It is a 6- to 18-membered aryl compound that has been optionally substituted at the base.

[0245] In this embodiment, R 1 teeth, [ka] And L is R 1 By replacing any hydrogen atom in R 1 Each R is coupled to it. 1 This is 1 to 3 R g It is being replaced by an arbitrary choice.

[0246] In this embodiment, R 1 teeth, [ka] That is the case.

[0247] In this embodiment, R 1 teeth, [ka] That is the case.

[0248] In this embodiment, R 1 teeth, [ka] That is the case.

[0249] In this embodiment, R 1 teeth, [ka] That is the case.

[0250] In this embodiment, R 1 teeth, [ka] That is the case.

[0251] In embodiments of the compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (XIV), or their pharmaceutically acceptable salts, or their deuterated forms, R 1 A monocyclic heterocycline is a 5-12 member monocyclic heterocycline containing a heteroatom selected from N, S, or O, and a monocyclic heterocycline contains 1-3 R g It is optionally substituted with the base. In the embodiment, R 1 teeth, [ka] And R 1 Each of these has 1 to 3 R g It is being replaced by an arbitrary choice.

[0252] In embodiments of the compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (XIV), or their pharmaceutically acceptable salts, or their deuterated forms, R 1 It is a 5-12 member monocyclic heteroaryl containing a heteroatom selected from N, S, or O, and each monocyclic heteroaryl contains 1-3 R g It is optionally substituted with the base. In the embodiment, R 1 teeth, [ka] Each of these has 1 to 3 R gIt is optionally substituted with the base. In the embodiment, R g These are independently H, halogen, C1-C6 alkyl, and OSO2C 1-6 It is alkyl or CN. In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] That is the case.

[0253] In embodiments of the compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (XIV), or their pharmaceutically acceptable salts, or their deuterated forms, R 1 It is a 7-14 membered bicyclic heteroaryl containing a heteroatom selected from N, S, or O, and the bicyclic heteroaryl contains 1-4 R g It is optionally substituted in the base.

[0254] In this embodiment, R 1 teeth, [ka] Each of these has 1 to 3 R g It is optionally substituted with the base. In the embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] That is the case.

[0255] In embodiments of the compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (XIV), or their pharmaceutically acceptable salts, or their deuterated forms, R 1 teeth, [ka] And, Y is independent of O, S, CHR 6 , or NR 6 And, R 6 However, due to one, two, or three F atoms, or OH, OC 1-6 Alkyl, N(C 1-6 C is optionally substituted with alkyl)2, cycloalkyl, or heterocyclyl. 1-6 It is alkyl.

[0256] In this embodiment, R 1 teeth, [ka] That is the case.

[0257] In embodiments of the compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (XIV), or their pharmaceutically acceptable salts, or their deuterated forms, R 1 teeth, [ka] And, X 4 However, NR 6 , O, CR 7 CR 14 R 15 , S, S(O), or S(O)2, Q is either CH or N, Each R 6 However, independently, H, C 1-6 Alkyl, -COC 1-6 Alkyl, C 2-6 Alkenil, C 2-6Alkinyl and C 3-6 Selected from cycloalkyl groups, alkyl, alkenyl, alkynyl, and cycloalkyl groups are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH. Each R 7 However, independently, H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CONHC 1-6 Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6 Selected from alkyl and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, or O, R 7 The alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups within are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH. R 14 and R 15 However, each is independent of H, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, cyano, hydroxyl, NH2, COOH, -S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6Selected from cycloalkyl groups, -SO2-3 to 7-membered heterocyclines, and 4 to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycles are optionally substituted with 1 to 3 groups selected from halogens, cyano, hydroxyl, NH2, and -COOH. Alternatively, R 14 and R 15 However, it forms =O.

[0258] In this embodiment, R 1 teeth, [ka] That is the case.

[0259] In this embodiment, R 1 teeth, [ka] That is the case.

[0260] In embodiments of the compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (XIV), or their pharmaceutically acceptable salts, or their deuterated forms, R 1 teeth, [ka] And, each X 4 However, independently, NR 6 , O, CR 14 R 15 , S, S(O), or S(O)2, Each R 6 However, independently, H, C 1-6 Alkyl, -COC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl and C 3-6Selected from cycloalkyl groups, alkyl, alkenyl, alkynyl, and cycloalkyl groups are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH. Each R 7 However, independently, H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, cyano, hydroxyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, COOH, COC 1-6 Alkyl, COOC 1-6 Alkyl, CONHC 1-6 Alkyl, CON(C 1-6 Alkyl)2, NHCOC 1-6 Selected from alkyl and 4-7 membered heterocycles containing 1-3 heteroatoms selected from N, S, or O, R 7 The alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups within are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH. R 14 and R 15 However, each is independent of H, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, cyano, hydroxyl, NH2, COOH, -S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6Selected from cycloalkyl groups, -SO2-3 to 7-membered heterocyclines, and 4 to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycles are optionally substituted with 1 to 3 groups selected from halogens, cyano, hydroxyl, NH2, and -COOH, or R 14 and R 15 However, it forms =O.

[0261] In the embodiment, [ka] That is the case.

[0262] In some embodiments, X 4 These are O, S, and NR, independently. 6 , or CR 14 R 15 That is the case.

[0263] In this embodiment, R 6 C 1-6 It is alkyl, C 1-6 Alkyl groups consist of one, two, or three F, OH, and OC atoms. 1-6 Alkyl, N(C 1-6 It is optionally substituted with alkyl)2, cycloalkyl, or heterocyclyl.

[0264] In this embodiment, the cycloalkyl is cyclopropyl.

[0265] In the embodiment, heterocyclyl is tetrahydropyran. In the embodiment, R 6 C 1-6 It is alkyl, and the C 1-6 The alkyl group is optionally substituted with one, two, or three F atoms.

[0266] In this embodiment, R 6 It is either methyl or ethyl.

[0267] In this embodiment, R 6 This is CH3.

[0268] In this embodiment, R 7 These are H, F, Cl, or CH3.

[0269] In this embodiment, R 7 H is H.

[0270] In this embodiment, R 7 is H, halo, or C 1-6 It is alkyl, R 14 and R 15 These are independently H, halo, or C 1-6 It is alkyl.

[0271] Control device, each X 4 These are independently NH, O, S, CHF, or CHF2.

[0272] In this embodiment, X 4 It is O.

[0273] In this embodiment, R 1 teeth, [ka] That is the case.

[0274] In this embodiment, R 1 teeth, [ka] That is the case.

[0275] In this embodiment, R 1 teeth, [ka] That is the case.

[0276] In this embodiment, R 1 teeth, [ka] That is the case.

[0277] In embodiments of the compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (XIV), or their pharmaceutically acceptable salts, or their deuterated forms, R 1 This is 1 to 4 R g The base is optionally replaced [ka] The ring C is a 7- to 8-membered heterocycle containing 1 to 3 heteroatoms selected from O, S, and N.

[0278] In this embodiment, R 1 teeth, [ka] And each of these has 1 to 4 R g It is optionally substituted in the base.

[0279] In this embodiment, R 1 teeth, [ka] That is the case.

[0280] In embodiments of the compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (XIV), or their pharmaceutically acceptable salts, or their deuterated forms, R 1 It is a 7-20 membered tricyclic heteroaryl containing a heteroatom selected from N, S, or O, and the tricyclic heteroaryl contains 1-5 R g It is being replaced by an arbitrary choice.

[0281] In embodiments of the compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (XIV), or their pharmaceutically acceptable salts, or their deuterated forms, R 1It is a 7-20 membered spirotricyclic heteroaryl containing a heteroatom selected from N, S, or O, and the tricyclic heteroaryl contains 1-5 R g It is being replaced by an arbitrary choice.

[0282] In embodiments of the compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (XIV), or their pharmaceutically acceptable salts, or their deuterated forms, R 1 teeth, [ka] And, Each R 6 However, independently, H, C 1-6 Alkyl, -COC 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Selected from cycloalkyl or alkylene-O-alkyl, the alkyl, alkenyl, alkynyl, and cycloalkyl groups are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH. R 14 and R 15 However, each is independent of H, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, cyano, hydroxyl, NH2, COOH, -S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6Selected from cycloalkyl groups, -SO2-3 to 7-membered heterocyclines, and 4 to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycles are optionally substituted with 1 to 3 groups selected from halogens, cyano, hydroxyl, NH2, and -COOH. Alternatively, R 14 and R 15 However, it forms =O.

[0283] In embodiments of the compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (XIV), or their pharmaceutically acceptable salts, or their deuterated forms, R 1 teeth, [ka] And, W, X4, and Y2 are each independently CH or N, provided that at most one of W, X4, and Y2 can be N. DE is N(H)-C(=O), N(C 1-6 It is alkyl)-C(=O), CH2CH2, C(=O)-O, or CH2-O, R 11 However, H, C 1-6 Alkyl, alkylene-O-alkyl, or heterocyclyl, i and j are independently 1, 2, or 3, provided that the sum of i + j is 2, 3, or 4.

[0284] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), or (XVI), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, W, X4, and Y2 are each independently CH or N, provided that at most one of W, X4, and Y2 can be N.

[0285] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), or (XVI), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, DE is N(H)-C(O), N(C 1-3 Selected from -alkyl)-C(O), CH2CH2, C(O)-O, and CH2-O.

[0286] In embodiments of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), or (XVI), or their pharmaceutically acceptable salts, or their deuterated forms, DE is N(H)-C(O), N(CH3)-C(O), CH2CH2, C(O)-O, or CH2-O.

[0287] In embodiments of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), or (XVI), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, DE is CH2-O.

[0288] In embodiments of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), or (XVI), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 11 This is H, alkylene-O-alkyl, or heterocyclyl.

[0289] In embodiments of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), or (XVI), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 11 It is H, CH3OCH2CH2, or heterocyclyl.

[0290] In embodiments of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), or (XVI), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 11 These are H, alkylene-O-alkyl, oxetanyl, tetrahydrofuranyl, 4-tetrahydropyranyl, or 3-tetrahydropyranyl.

[0291] In embodiments of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), or (XVI), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 11 H, C 1-3 -Alkyl, CH3OCH2CH2, oxetanyl, tetrahydrofuranyl, 4-tetrahydropyranyl, or 3-tetrahydropyranyl. In embodiments of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), or (XVI), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 11 This is H, CH3-, or oxetanyl.

[0292] In embodiments of compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), or (XVI), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, i and j are each independently 1, 2, or 3, provided that the sum of i + j is 2, 3, or 4.

[0293] In embodiments of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), or (XVI), or pharmaceutically acceptable salts thereof, or deuterated forms thereof, R 11 is H, CH3, or oxetanyl, W is CH or N, X4 is CH or N, Y2 is CH, provided that at most one of W, X, and Y can be N, DE is selected from N(CH3)-C(O), CH2CH2, C(O)-O, and CH2-O, i is 1 or 2, and j is 1 or 2, provided that the sum of i + j is 2, 3, or 4.

[0294] In embodiments of the compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (XIV), or their pharmaceutically acceptable salts, or their deuterated forms, R 1 teeth, [ka] That is the case.

[0295] In this embodiment, R 1 teeth, [ka] That is the case.

[0296] In embodiments of the compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (XIV), or their pharmaceutically acceptable salts, or their deuterated forms, R 1 It is a 7-20 membered condensed tricyclic heteroaryl containing a heteroatom selected from N, S, or O, and the tricyclic heteroaryl contains 1-5 R g It is being replaced by an arbitrary choice.

[0297] In embodiments of the compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (XIV), or their pharmaceutically acceptable salts, or their deuterated forms, R 1 but, [ka] And each of these has 1 to 5 R g It is optionally replaced by R 14 and R 15 However, each is independent of H, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, cyano, hydroxyl, NH2, COOH, -S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2C 3-6 Selected from cycloalkyl groups, -SO2-3 to 7-membered heterocyclines, and 4 to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycles are optionally substituted with 1 to 3 groups selected from halogens, cyano, hydroxyl, NH2, and -COOH. Each R 6 However, independently, H, C 1-6 Alkyl, -COC 1-6 Alkyl, C 2-6Alkenil, C 2-6 Alkinyl, C 3-6 Selected from cycloalkyl or alkylene-O-alkyl, the alkyl, alkenyl, alkynyl, and cycloalkyl groups are optionally substituted with 1 to 3 groups selected from halogen, cyano, hydroxyl, NH2, and COOH. Ring D is selected from a 5-8 membered heteroaryl containing an aryl and 1-3 heteroatoms, and each of these 5-8 membered heteroaryls containing an aryl and 1-3 heteroatoms independently contains 1-3 R g It is optionally substituted with. In this embodiment, ring D is [ka] Each of these has 1 to 3 R g It is optionally substituted with the base. In the embodiment, R 1 teeth, [ka] [ka] That is the case.

[0298] In embodiments, compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or deuterated forms thereof are provided herein.

[0299] In embodiments, pharmaceutically acceptable salts of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX) are provided herein. Further embodiments of the present invention relate to deuterated compounds of (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or pharmaceutically acceptable salts thereof, or deuterated forms thereof.

[0300] In embodiments, the compounds of Table 1, or pharmaceutically acceptable salts thereof, or deuterated forms thereof, or stereoisomers thereof are provided herein. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22

[0301] Components Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), or (XVI), or the compounds in Table 1, or their pharmaceutically acceptable salts, or deuterated versions thereof, may be used on their own, but generally, formulas (I), (II), or (III), (III-A), (III-B), or the compounds / salts in Table 1 (active ingredient) are administered in the form of pharmaceutical compositions in which they are associated with pharmaceutically acceptable adjuvants, diluents, or carriers. Conventional procedures for the selection and preparation of appropriate pharmaceutical formulations are described, for example, in “Pharmaceuticals—The Science of Dosage Form Designs”, MEAulton, Churchill Livingstone, 2nd Ed. 2002.

[0302] In embodiments, the present disclosure provides pharmaceutical compositions comprising, as defined above in relation to a pharmaceutically acceptable adjuvant, diluent, or carrier, formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), or (XVI), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, or a deuterated form thereof.

[0303] The Disclosure further provides a process for preparing the pharmaceutical compositions of the Disclosure, comprising mixing formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), or (XVI), or the compounds of Table 1, or pharmaceutically acceptable salts thereof, or deuterated forms thereof, as defined above in relation to pharmaceutically acceptable adjuvants, diluents, or carriers.

[0304] Pharmaceutical compositions may be administered topically (e.g., to the skin or to the lungs and / or airways) in the form of, for example, creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powder formulations (e.g., formulations in inhalation devices known as Turbuhaler®), or systemically by, for example, oral administration in the form of tablets, capsules, syrups, powders or granules, or parenteral administration in the form of sterile solutions, suspensions or emulsions for injection (including intravenous, subcutaneous, intramuscular, intravascular or intra-infusion), or rectal administration in the form of suppositories.

[0305] For oral administration, the compounds of this disclosure may be mixed with adjuvants, diluents, or carriers, such as lactose, saccharose, sorbitol, mannitol; starches, such as potato starch, corn starch, or amylopectin; cellulose derivatives; binders, such as gelatin or polyvinylpyrrolidone; disintegrants, such as cellulose derivatives, and / or lubricants, such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, etc., and then compressed into tablets. If coated tablets are required, the cores prepared as described above may be coated with a suitable polymer dissolved or dispersed in water or a readily volatile organic solvent. Alternatively, the tablets may be coated with a concentrated sugar solution, which may contain, for example, gum arabic, gelatin, talc, and titanium dioxide.

[0306] For the preparation of soft gelatin capsules, the compounds of this disclosure may be mixed with, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compounds using pharmaceutical excipients, such as the excipients for tablets. Furthermore, liquid or semi-solid formulations of the compounds of this disclosure may be filled into hard gelatin capsules.

[0307] Liquid formulations for oral administration may be in the form of syrup, solution, or suspension. A solution may, for example, contain the compounds of this disclosure, with the remainder being a mixture of sugar, ethanol, water, glycerol, and propylene glycol. Optionally, such liquid formulations may contain colorants, flavorings, saccharin, and / or carboxymethylcellulose as thickeners. Furthermore, when preparing formulations for oral use, other excipients known to those skilled in the art may be used.

[0308] therapeutic use In embodiments, formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or the compounds in Table 1, and their pharmaceutically acceptable salts, are DPP1 inhibitors and can therefore be used in any disease area in which DPP1 plays a role. Accordingly, in one aspect of the present invention, a method of treatment is provided. In one embodiment, the treatment method involves administering to a subject in need of treatment an effective amount of a composition containing formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or a compound from Table 1, or a pharmaceutically acceptable salt of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or a pharmaceutically acceptable salt from Table 1. In this embodiment, the composition is administered to the patient over a period of administration.

[0309] In embodiments, the compounds or compositions of the present disclosure are used to treat patients with obstructive airway diseases, chronic sinusitis (CRS), hidradenitis suppurativa (HS), cancer (e.g., metastatic cancer), granulomatous diseases with polyangiitis (GPA), microscopic polyangiitis (MPA), giant cell arteritis, polyarteritis nodosa, anti-GBM diseases (Goodpasture's disease), rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, systemic sclerosis, inflammatory bowel disease (IBD) (e.g., ulcerative colitis). It is administered in ways to treat Crohn's disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic ulcers, Duchenne muscular dystrophy, bronchiolitis obliterans, post-COVID-19 sequelae (ILD) - prevention of ILD, atopic dermatitis, pyoderma gangrenosum, Sweet's syndrome, dermatomyositis / polymyositis, neutrophilic dermatitis, uveitis, Behçet's disease, thrombosis, bronchopulmonary dysplasia, amyotrophic lateral sclerosis, sickle cell anemia, psoriasis, and ventilator-induced lung injury.

[0310] In embodiments, the compounds or compositions of the present disclosure are administered to a patient in a manner for treating an obstructive airway disease. In one embodiment, the obstructive airway disease is asthma (e.g., bronchial, allergic, endogenous, exogenous, exercise-induced, drug-induced (including aspirin and NSAID-induced asthma, and dust-induced asthma, both intermittent and persistent, and of all severity) airway hypersensitivity, chronic obstructive pulmonary disease (COPD), bronchitis (e.g., infectious bronchitis, eosinophilic bronchitis), emphysema, cystic fibrosis (CF), bronchiectasis (e.g., non-CF bronchiectasis (NCFBE) and CF-associated bronchiectasis), cystic fibrosis, s Antitussive effects include the treatment of chronic cough associated with inflammatory and secretory conditions of the airways, including lucoidosis, alpha-1 antitrypsin (A1AT) deficiency, farmer's lung and related diseases, hypersensitivity pneumonitis, interstitial lung disease, pulmonary fibrosis (including idiopathic pulmonary fibrosis, idiopathic fibrotic alveolitis, idiopathic interstitial pneumonia, fibrosis associated with antitumor therapy and chronic infections (including tuberculosis and aspergillosis and other fungal infections)), complications of lung transplantation, vascular and thrombotic disorders of the pulmonary vascular system, pulmonary hypertension (e.g., pulmonary arterial hypertension), and chronic cough associated with inflammatory and secretory conditions of the airways. Acute and chronic rhinitis, including iatrogenic cough, drug-induced rhinitis and vasomotor rhinitis; perennial and seasonal allergic rhinitis (hay fever), including neurogenic rhinitis; nasal polyps; acute viral infections, including the common cold; and infections caused by respiratory viruses (e.g., respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus); acute lung injury; acute respiratory distress syndrome (ARDS); and exacerbations of any of the aforementioned respiratory and tracheal conditions.

[0311] Cystic fibrosis (CF) is caused by abnormalities in CF transmembrane conductance regulatory factor proteins, leading to chronic lung infections (particularly by Pseudomonas aeruginosa) and excessive inflammation, resulting in bronchiectasis, decreased lung function, respiratory failure, and poor quality of life. The inflammatory process is dominated by neutrophils that produce NE, as well as other destructive NSPs, including CatG and PR3, which act directly on extracellular matrix proteins and are involved in the host response to inflammation and infection (Dittrich et al., Eur Respir J. 2018; 51(3)). The method provided herein uses a reversible inhibitor of DPP1. While we do not wish to be bound by theory, it is thought that compounds of formula (I), (II), or (III) administered via the method provided herein have beneficial effects by inhibiting NSP activation and reducing inflammation, which in turn leads to a reduction in lung exacerbations, a decrease in the rate of lung exacerbations, and / or improvement in lung function (e.g., forced expiratory volume in one second [FEV1]) in CF patients.

[0312] In one embodiment, a method for treating CF is provided, comprising administering to a CF patient in need of treatment an effective amount of a composition comprising a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or a pharmaceutically acceptable salt thereof, or a deuterated form thereof.

[0313] In one method of treating CF, a composition comprising an effective amount of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or a pharmaceutically acceptable salt thereof, or a deuterated form thereof, is administered to a CF patient requiring treatment for a period of administration. This method involves improving the patient's lung function during the administration period compared to the patient's lung function before the administration period. In one embodiment, the improvement in lung function is measured by vital capacity measurement.

[0314] In one embodiment, improving a patient's lung function involves increasing the patient's forced expiratory volume per second (FEV1), the patient's forced vital capacity (FVC), the patient's maximum expiratory flow rate (PEFR), or the patient's forced expiratory flow rate (FEF) by 25% to 75% of the patient's FVC, compared to the respective values ​​prior to the administration period. (25~75%) This includes increasing ) the respective values. In one embodiment, the increase is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% of the respective values. In one embodiment, the increase is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%. In yet another embodiment, the increase is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20%. In yet another embodiment, the increase is about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, or about 25% to about 50%.

[0315] In one embodiment of the method provided herein, a composition comprising an effective amount of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX), or a pharmaceutically acceptable salt thereof, or a deuterated form thereof, is administered to a patient with bronchiectasis requiring treatment for a period of administration. Bronchiectasis is considered a pathological endpoint arising from many disease processes and is a persistent or progressive condition characterized by dilation of the thick-walled bronchi. Symptoms range from intermittent episodes of sputum and infection localized in the affected areas of the lungs to persistent daily sputum, often of large amounts of purulent sputum. Bronchiectasis may be associated with other nonspecific respiratory symptoms. While we do not wish to be bound by theory, the underlying pathological processes of bronchiectasis have been reported as airway damage resulting from an event or set of events in which inflammation is central to the process (Guideline for non-CF Bronchiectasis, Thorax, July 2010, V.65(Suppl 1), which is incorporated herein by reference in its entirety for all purposes).

[0316] Bronchiectasis is considered a pathological endpoint arising from many disease processes and is a persistent or progressive condition characterized by dilation of the thick-walled bronchi. Symptoms range from intermittent episodes of sputum and infection localized in the affected lung area to persistent daily sputum, often of large amounts of purulent sputum. Bronchiectasis may be associated with other nonspecific respiratory symptoms. While we do not wish to be bound by theory, the underlying pathological processes of bronchiectasis have been reported as damage to the airways resulting from an event or set of events in which inflammation is central to the process (Guideline for non-CF Bronchiectasis, Thorax, July 2010, V.65(Suppl 1), which is incorporated herein by reference in its entirety for all purposes).

[0317] The methods provided herein utilize reversible inhibitors of DPP1. While we do not wish to be bound by theory, the compounds of formula (I), (II), or (III) administered via the methods provided herein are thought to have beneficial effects by reducing inflammation and mucus hypersecretion, which in some embodiments is thought to result in reduced lung exacerbations, a decrease in the rate of lung exacerbations, and / or improved lung function (cough, sputum production, and forced expiratory volume per second (FEV1)) in patients with bronchiectasis. While we do not wish to be bound by theory, the methods provided herein are thought to improve the progression of bronchiectasis by reducing the rate of lung function decline or lung tissue destruction.

[0318] In one embodiment, bronchiectasis is non-CF bronchiectasis.

[0319] In one embodiment, a method for treating bronchiectasis includes improving the patient's lung function during the administration period compared to the patient's lung function before the administration period.

[0320] In one embodiment, lung exacerbation is characterized by three or more of the following symptoms, presented by the patient for at least 48 hours: (1) increased cough, (2) increased sputum volume or altered sputum viscosity, (3) increased sputum purulence, (4) increased shortness of breath and / or decreased exercise tolerance, (5) fatigue and / or malaise, and (6) hemoptysis. In a further embodiment, three or more symptoms lead the physician to decide to prescribe antibiotics to the symptomatic patient.

[0321] In one embodiment of a method for treating bronchiectasis, the method comprises reducing the rate of lung exacerbation in a subject compared to the rate of lung exacerbation experienced by the subject before the period of administration of the composition, or compared to a control subject having bronchiectasis that has not been subjected to the method of treatment. In a further embodiment, the bronchiectasis is non-CF bronchiectasis.

[0322] In another embodiment, a method is provided for treating chronic sinusitis (CRS) in a subject requiring treatment. In one embodiment, the method comprises administering to a subject a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II), or (III), a pharmaceutically acceptable salt thereof, or a deuterated form thereof, over a period of administration.

[0323] Chronic sinusitis is either chronic sinusitis without nasal polyps (CRSsNP) or chronic sinusitis with nasal polyps (CRSwNP). In some embodiments, chronic sinusitis is chronic sinusitis without nasal polyps (CRSsNP). In some embodiments, chronic sinusitis is chronic sinusitis with nasal polyps (CRSwNP). In some embodiments, chronic sinusitis is refractory chronic sinusitis. In some embodiments, refractory chronic sinusitis is refractory chronic sinusitis without nasal polyps (CRSsNP). In some embodiments, refractory chronic sinusitis is refractory chronic sinusitis with nasal polyps (CRSwNP).

[0324] In some embodiments, the subject exhibits one or more symptoms of CRS. In some embodiments, one or more symptoms of CRS are (a) nasal congestion, (b) nasal obstruction, (c) runny nose, (d) postnasal drip, (e) facial pressure, (f) facial pain, (g) facial bloating, (h) decreased sense of smell, (i) depression, (j) mucosal edema, (k) mucopurulent discharge, (l) middle meatus obstruction, (m) mucosal changes in the natural middle meatus route and sinuses, (n) rhinorrhea, or (o) any combination thereof. In some embodiments, middle meatus obstruction is mucosal obstruction, edematous obstruction, or a combination thereof.

[0325] In some embodiments, administration of the pharmaceutical composition reduces, decreases the severity of, delays the onset of, or eliminates one or more symptoms of CRS. In some embodiments, one or more symptoms of CRS are (a) nasal congestion, (b) nasal obstruction, (c) runny nose, (d) postnasal drip, (e) facial pressure, (f) facial pain, (g) facial bloating, (h) decreased sense of smell, (i) depression, (j) mucosal edema, (k) mucopurulent discharge, (l) middle meatus obstruction, (m) mucosal changes in the natural middle meatus route and sinuses, (n) rhinorrhea, (o) or any combination thereof. In some embodiments, administration of the pharmaceutical composition enhances sinus drainage.

[0326] In some embodiments, the method includes reducing the composite severity score of one or more symptoms of CRS. As used herein, “composite severity score” is a quantitative measure of all symptoms of CRS presented by the subject. In some embodiments, the composite severity score is the sum of all daily symptoms presented by the subject. In some embodiments, the composite severity score is reduced during or after the administration period compared to the composite severity score measured before the administration period. In some embodiments, the one or more symptoms of CRS presented by the subject may be any symptoms described herein or known in the art to be related to CRS. In some embodiments, the one or more symptoms of CRS may be nasal congestion, odor reduction, runny nose, or any combination thereof. In some embodiments, the runny nose is anterior rhinorrhea. In some embodiments, the runny nose is posterior rhinorrhea.

[0327] In some embodiments, the method includes reducing the subject's Sino-Nasal Outcome Test-22 (SNOT-22) score during or after the administration period compared to the subject's SNOT-22 score before the administration period. As used herein, “SNOT-22” is a patient-reported outcome measure developed for use in CRS with or without nasal polyps, and comprises 22 individual questions. The questions cover a wide range of health and health-related quality of life issues, including physical problems, functional limitations, and emotional outcomes. The theoretical range of SNOT-22 scores is 0 to 110, with lower scores indicating better health-related quality of life. Further details of SNOT-22 are provided in Hopkins, et al., Clin. Otolaryngol. 2009, 34, 447-454 and Kennedy, et al., Ann Allergy Asthma Immunol. 2013 October;111(4):246-251, the contents of which are incorporated herein by reference in their entirety.

[0328] Sweat gland abscesses (HS) are a chronic, recurrent inflammatory disorder. Symptoms often involve skin lesions associated with hair follicles, which can be painful, inflamed, and / or swollen. Even after the skin lesions have healed, they can sometimes recur, potentially leading to tunnels under the skin and progressive scarring. Because HS is a chronic condition, it can persist for many years and worsen over time, significantly impacting quality of life and psychological and emotional health. Indeed, patients with HS have an increased rate of anxiety and depression, with a suicide risk 2.5 times higher than in the general population.

[0329] HS patients are classified into mild (stage I), moderate (stage II), or severe (stage III) according to the severity of the disease, known as the Hurley stage. While over 200,000 cases of HS are diagnosed annually in the United States, the disease can be difficult to diagnose and requires specialized care. HS can be mistaken for infections, ingrown hairs, or other conditions. Furthermore, current treatment options are limited and often ineffective.

[0330] In one embodiment, a method is provided for treating HS in a subject requiring treatment. In one embodiment, the method comprises administering to the subject a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II), or (III), a pharmaceutically acceptable salt thereof, or a deuterated form thereof, over a period of administration. In a further embodiment, the method for treating HS comprises reducing neutrophilic inflammation in the subject.

[0331] In one embodiment, HS is a stage I HS, a stage II HS, or a stage III HS. In some embodiments, HS is a stage I HS. In some embodiments, HS is a stage II HS. In some embodiments, HS is a stage III HS.

[0332] This disclosure provides a method for treating cancer in a subject requiring cancer treatment, the method comprising administering a pharmaceutical composition containing an effective amount of any one of the compounds disclosed herein to the subject. This disclosure also provides a method for treating cancer-induced pain in a subject having cancer, comprising administering a pharmaceutical composition containing an effective amount of any one of the compounds disclosed herein to the subject for a period of administration. In some embodiments, cancer-induced pain is cancer-induced bone pain. This disclosure also provides a method for treating cancer-induced bone pain in a subject having cancer, comprising administering a pharmaceutical composition containing an effective amount of any one of the compounds disclosed herein to the subject for a period of administration.

[0333] In some embodiments, cancer includes primary solid tumors. In some embodiments, cancer is bladder cancer, lung cancer, brain cancer, ovarian cancer, pancreatic cancer, colorectal cancer, prostate cancer, liver cancer, hepatocellular carcinoma, kidney cancer, stomach cancer, skin cancer, fibroid cancer, lymphoma, virus-induced cancer, oropharyngeal cancer, testicular cancer, thymic cancer, thyroid cancer, melanoma, or bone cancer.

[0334] In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is stomach cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is fibroid carcinoma. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is virus-induced cancer. In some embodiments, the cancer is oropharyngeal cancer. In some embodiments, the cancer is testicular cancer. In some embodiments, the cancer is thymic carcinoma. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is bone cancer. In some embodiments, fibroid carcinoma is leiomyosarcoma.

[0335] In some embodiments, breast cancer includes tubular carcinoma, lobular carcinoma, medullary carcinoma, gelatinous carcinoma, tubular carcinoma, or inflammatory breast cancer. In some embodiments, breast cancer includes tubular carcinoma. In some embodiments, breast cancer includes lobular carcinoma. In some embodiments, breast cancer includes medullary carcinoma. In some embodiments, breast cancer includes gelatinous carcinoma. In some embodiments, breast cancer includes tubular carcinoma. In some embodiments, breast cancer includes inflammatory breast cancer.

[0336] In some embodiments, the breast cancer is triple-negative breast cancer. In some embodiments, the breast cancer does not respond to hormone therapy or therapeutic agents that target the HER2 protein receptor.

[0337] In some embodiments, the lymphoma is Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma, natural killer cell lymphoma, T-cell lymphoma, Burkitt lymphoma, or Kaposi's sarcoma. In some embodiments, the lymphoma is Hodgkin lymphoma. In some embodiments, the lymphoma is non-Hodgkin lymphoma. In some embodiments, the lymphoma is diffuse large B-cell lymphoma. In some embodiments, the lymphoma is B-cell immunoblastic lymphoma. In some embodiments, the lymphoma is natural killer cell lymphoma. In some embodiments, the lymphoma is T-cell lymphoma. In some embodiments, the lymphoma is Burkitt lymphoma. In some embodiments, the lymphoma is Kaposi's sarcoma.

[0338] In some embodiments, brain cancer is an astrocytoma, an undifferentiated astrocytoma, glioblastoma pleomorphic, oligodendroglioma, ependymoma, meningioma, schwannoma, or medulloblastoma. In some embodiments, brain cancer is an astrocytoma. In some embodiments, brain cancer is an undifferentiated astrocytoma. In some embodiments, brain cancer is a glioblastoma pleomorphic. In some embodiments, brain cancer is an oligodendroglioma. In some embodiments, brain cancer is an ependymoma. In some embodiments, brain cancer is a meningioma. In some embodiments, brain cancer is a schwannoma. In some embodiments, brain cancer is a medulloblastoma.

[0339] In some embodiments, the cancer is a humoral tumor. In some embodiments, the humoral tumor is acute myeloid leukemia (AML), acute lymphoblastic leukemia, acute lymphoblastic leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myeloproliferative disorder, natural killer cell leukemia, blastic plasmacytoid dendritic cell neoplasm, chronic myeloid leukemia (CML), mast cell disease, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), or myelodysplastic syndrome (MDS). In some embodiments, the humoral tumor is acute myeloid leukemia (AML). In some embodiments, the humoral tumor is acute lymphoblastic leukemia. In some embodiments, the humoral tumor is acute lymphoblastic leukemia. In some embodiments, the humoral tumor is acute promyelocytic leukemia. In some embodiments, the humoral tumor is chronic myeloid leukemia. In some embodiments, the humoral neoplasm is hairy cell leukemia. In some embodiments, the humoral neoplasm is myeloproliferative disorder. In some embodiments, the humoral neoplasm is natural killer cell leukemia. In some embodiments, the humoral neoplasm is blastic plasmacytoid dendritic cell neoplasm. In some embodiments, the humoral neoplasm is chronic myeloid leukemia (CML). In some embodiments, the humoral neoplasm is mast cell disease. In some embodiments, the humoral neoplasm is chronic lymphocytic leukemia (CLL). In some embodiments, the humoral neoplasm is multiple myeloma (MM). In some embodiments, the humoral neoplasm is myelodysplastic syndrome (MDS).

[0340] In some embodiments, the cancer is childhood cancer. In some embodiments, the childhood cancer is neuroblastoma, Wilms' tumor, rhabdomyosarcoma, retinoblastoma, osteosarcoma, or Ewing's sarcoma. In some embodiments, the childhood cancer is neuroblastoma. In some embodiments, the childhood cancer is Wilms' tumor. In some embodiments, the childhood cancer is rhabdomyosarcoma. In some embodiments, the childhood cancer is retinoblastoma. In some embodiments, the childhood cancer is osteosarcoma. In some embodiments, the childhood cancer is Ewing's sarcoma.

[0341] In some embodiments, the cancer is metastatic cancer. In some embodiments, the subject is at risk of developing metastatic cancer. In some embodiments, metastatic cancer includes metastases of breast cancer to the brain, bone, pancreas, lymph nodes, and / or liver. In some embodiments, metastatic cancer includes metastases of bone cancer to the lungs. In some embodiments, metastatic cancer includes metastases of colorectal cancer to the peritoneum, pancreas, stomach, lungs, liver, kidneys, and / or spleen. In some embodiments, metastatic cancer includes metastases of gastric cancer to the mesentery, spleen, pancreas, lungs, liver, adrenal glands, and / or ovaries. In some embodiments, metastatic cancer includes metastases of leukemia to the lymph nodes, lungs, liver, hind limbs, brain, kidneys, and / or spleen. In some embodiments, metastatic cancer includes metastases of liver cancer to the intestines, spleen, pancreas, stomach, lungs, and / or kidneys. In some embodiments, metastatic cancer includes metastases of lymphoma to the kidneys, ovaries, liver, bladder, and / or spleen.

[0342] In some embodiments, metastatic cancer includes metastases of hematopoietic cancer to the intestines, lungs, liver, spleen, kidneys, and / or stomach. In some embodiments, metastatic cancer includes metastases of melanoma to lymph nodes and / or lungs. In some embodiments, metastatic cancer includes metastases of pancreatic cancer to the mesentery, ovaries, kidneys, spleen, lymph nodes, stomach, and / or liver. In some embodiments, metastatic cancer includes metastases of prostate cancer to the lungs, pancreas, kidneys, spleen, intestines, liver, bones, and / or lymph nodes. In some embodiments, metastatic cancer includes metastases of ovarian cancer to the diaphragm, liver, intestines, stomach, lungs, pancreas, spleen, kidneys, lymph nodes, and / or uterus. In some embodiments, metastatic cancer includes metastases of myeloma to bones.

[0343] In some embodiments, metastatic cancer includes metastases of lung cancer to the bones, brain, lymph nodes, liver, ovaries, and / or intestines. In some embodiments, metastatic cancer includes metastases of kidney cancer to the liver, lungs, pancreas, stomach, brain, and / or spleen. In some embodiments, metastatic cancer includes metastases of bladder cancer to the bones, liver, and / or lungs. In some embodiments, metastatic cancer includes metastases of thyroid cancer to the bones, liver, and / or lungs.

[0344] In some embodiments, the methods disclosed herein include treating cancer-induced bone pain (CIBP) in subjects having cancer metastases to the bone. In some embodiments, the subjects have metastases to the bone of prostate cancer, breast cancer, lung cancer, or myeloma. In some embodiments, the subjects are identified as having metastases to the bone by the use of any one of the following methods: plain film radiography, computed tomography, technetium-99m bone scan, magnetic resonance imaging, fluorodeoxyglucose positron emission tomography, fluorine positron emission tomography, and / or choline positron emission tomography, but are not yet experiencing cancer-induced bone pain. In some embodiments, the subjects are suffering from cancer-induced bone pain, which indicates metastases to the bone of a previously treated or untreated primary tumor. In some embodiments, the cancer has metastasized to the vertebrae, pelvis, long bones, or ribs.

[0345] In some embodiments, administration of the composition reduces the severity of cancer, delays the onset of cancer, or eliminates cancer symptoms. In some embodiments, the cancer symptom is cancer-induced bone pain (CIBP). In some embodiments, CIBP is neuropathic pain. In some embodiments, CIBP is inflammatory pain. In some embodiments, CIBP is spontaneous pain. In some embodiments, the cancer symptom is nociceptive hypersensitivity. In some embodiments, the cancer symptom is allodynia. In some embodiments, allodynia is tactile allodynia. In some embodiments, tactile allodynia is static mechanical allodynia. In some embodiments, tactile allodynia is dynamic mechanical allodynia. In some embodiments, the subject has bone cancer or metastases to the bone.

[0346] In yet another embodiment of the present invention, a method is provided for treating lupus nephritis (LN) in a subject requiring treatment. The method comprises administering to the subject a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II), or (III), a pharmaceutically acceptable salt thereof, or a deuterated form thereof, over a period of administration.

[0347] Rheumatoid arthritis (RA) is characterized by inflammation and thickening of the joint capsule, along with effects on the underlying bone and cartilage. Currently, the cause of RA is unknown, and there is no satisfactory treatment for RA available. Several therapeutic agents have been developed and are used to alleviate disease-related pain and inflammation, such as disease-modifying antirheumatic drugs (DMARDs) and nonsteroidal anti-inflammatory drugs (NSAIDs), but they often result in unbearable side effects. To address this and other needs, the present invention provides, in one embodiment, a method for treating RA using a reversible inhibitor of DPP1 of formula (I), (II), or (III). In one embodiment, a method is provided for treating RA in a subject requiring treatment of RA, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, or a deuterated form thereof, over a period of administration. In a further embodiment, the method comprises reducing neutrophilic inflammation in the subject.

[0348] Inflammatory bowel disease (IBD) is a group of inflammatory conditions affecting the colon and small intestine. The most common IBDs are Crohn's disease and ulcerative colitis. In one embodiment, the present invention addresses the need for novel IBD therapies. Specifically, in one embodiment, a method is provided for doing so in a subject requiring treatment for inflammatory bowel disease (IBD). The method comprises administering to the subject a pharmaceutical composition comprising an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a deuterated form thereof, over a period of administration.

[0349] In further embodiments, IBD is Crohn's disease or ulcerative colitis. In further embodiments, the method includes reducing neutrophilic inflammation in the subject.

[0350] In any case, the length of the administration period may be determined by a physician, depending on the nature and severity of the condition being treated and / or prevented. In one embodiment, the administration period begins around the time of diagnosis of the condition / disease and continues throughout the patient's lifetime. [Examples]

[0351] The present invention will be further described by reference to the following embodiments. However, it should be noted that these embodiments, like the embodiments described above, are illustrative and should not be construed as limiting the scope of the present invention in any way.

[0352] In embodiments, the compounds of the present invention can be synthesized using the following methods. General reaction conditions are given, and the reaction products can be purified by commonly known methods, including silica gel chromatography or preparative reverse-phase high-pressure liquid chromatography using various organic solvents such as hexane, dichloromethane, ethyl acetate, and methanol.

[0353] In the following examples, the term “assumed” refers to the specific stereochemistry of each product, where present. Further characterization will confirm the absolute stereochemistry of the product.

[0354] General experiment 1 H NMR analysis: 1 The H-NMR spectrum is recorded using a Bruker Ultrashield (400 MHz). The signal multiplicity is specified by the following abbreviations: s, singlet; d, doublet; t, triplet; q, quadruplet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet.

[0355] All observed coupling constants J are reported in Hertz (Hz).

[0356] Interchangeable protons are not always observed.

[0357] LC / MS analysis: LC / MS method AN01_001_012: LC-MS data were generated using the Waters Acquity system: TUV detector, SQD2 MS detector, and Sedere SEDEX 80 (light scattering detector).

[0358] LC-MS method: Reversed phase HPLC analysis

[0359] Column Agilent: Cortex C18

[0360] Solvent A: Water containing formic acid (0.1% V / V)

[0361] Solvent B: Acetonitrile

[0362] Gradient table: [Table 4]

[0363] LC / MS method AN01_001_026: LC-MS data were generated using the Waters Acquity system: TUV detector, SQD2 MS detector, and Sedere SEDEX 80 (light scattering detector).

[0364] LC-MS method: Reversed phase HPLC analysis

[0365] Column Agilent:Poroshell

[0366] Solvent A: Water containing formic acid (0.1% V / V)

[0367] Solvent B: Acetonitrile

[0368] Gradient table: [Table 3] UV detection: 220nm

[0369] General synthesis procedure Procedure A To an argon-purged solution of the protective alcohol (1 equivalent) in EtOH (4.78 mL per 1 mmol of protective alcohol), 10% Pd / C (0.1 equivalent) is added at room temperature. The resulting mixture is purged with argon (3 times) and then with H2 (3 times). The reaction mixture is stirred at room temperature under atmospheric pressure with H2 for 18 hours. The reaction mixture is purged with argon, filtered through a Celite pad, and rinsed with EtOH (3 × 5 mL). The filtrate is concentrated under reduced pressure to obtain the expected compound.

[0370] Procedure B To a solution of an alcohol derivative (1 equivalent) in acetone (16.7 mL per 1 mmol of alcohol) and sodium bromide (0.3 equivalents), a saturated aqueous solution of NaHCO3 (2.59 mL per 1 mmol of alcohol) was added at room temperature. Trichlorocyanuric acid (2.2 equivalents) and 2,2,6,6-tetramethylpiperidine-1-oxyl (0.03 equivalents) were added to the resulting mixture at 0°C. The reaction mixture was heated to room temperature and stirred for 18 hours. Isopropanol (10 mL) was added at room temperature, and the reaction mixture was stirred for 30 minutes. The reaction mixture was diluted with HCl (50 mL), and a saturated aqueous solution of NaHCO3 (50 mL) was added. The two layers were separated, and the aqueous layer was washed with HCl (50 mL). The aqueous layer was then acidified to approximately pH 1 with 3 M aqueous HCl and extracted with DCM (2 × 50 mL). The combined organic layers are dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired compound.

[0371] Step C To a solution of an amine derivative (1 equivalent) and a carboxylic acid derivative (1.05 equivalents) in anhydrous DMF (7.14 mL per 1 mmol of amine), DIPEA (2.5 equivalents) and TBTU (1.5 equivalents) are added at room temperature under an argon atmosphere. The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is diluted with toluene (10 mL) and water (10 mL). The aqueous layer is extracted with toluene (2 × 10 mL), the combined organic layers are washed with brine (3 × 10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product is purified by flash chromatography over SiO₂ (see conditions for each compound) to obtain the desired compound.

[0372] Step D Add 7.6 mL / mmol of formic acid (also preheated to 50°C) to a preheated vial (50°C) containing 1 equivalent of a Boc-protected amine derivative. Stir the reaction mixture at 50°C for 15 minutes. Cool the reaction mixture to room temperature and add it dropwise to a stirred and cooled mixture (0°C) of saturated NaHCO3 aqueous solution (40 mL) and DCM (40 mL). Separate the layers and extract the aqueous layer with DCM (2 × 40 mL). Dry the combined organic layers over Na2SO4, filter, and concentrate under reduced pressure. Purify the crude product by flash chromatography and / or preparative HPLC (see conditions for each compound) to obtain the desired compound.

[0373] Step E To a solution of an alcohol derivative (1 equivalent) in anhydrous DMF (5.49 mL per 1 mmol of alcohol derivative) and iodomethane (2 equivalents), 60% NaH in oil (1.1 equivalents) is added at 0°C under an argon atmosphere. The resulting mixture is warmed to room temperature and stirred for 22 hours. The reaction mixture is quenched with saturated aqueous NH4Cl (10 mL) at room temperature. Then, siRNA (50 mL) and water (50 mL) are added to separate the two layers. The aqueous layer is extracted with siRNA (2 × 50 mL), and the combined organic layers are dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue is purified by silica gel flash chromatography (see conditions for each compound) to obtain the desired compounds.

[0374] Example 1: Preparation of B1-46-1-(S)* and B1-46-1-(R)* [ka] tert-butyl N-[(2S)-2,3-dihydroxypropyl]carbamate (B1-2-2) [ka] A solution of (2S)-3-aminopropane-1,2-diol (1 equivalent, 14.4 g, 158.1 mmol) and Et3N (1.01 equivalent, 22.2 mL, 159.6 mmol) in anhydrous MeOH (245 mL) was mixed with a solution of Boc2O (1.2 equivalents, 41.4 g, 189.7 mmol) in anhydrous DCM (41 mL) at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure to obtain B1-2-2 as a pale yellow oil (30.2 g, quantitative). The crude product was considered quantitative and was used as is.

[0375] LC / MS (AN01_001_012): Rt=1.69 min, non-UV active, [M+Na] + = 214.1.

[0376] tert-butyl N-[(2S)-3-(benzyloxy)-2-hydroxypropyl]carbamate (B1-2-3) [ka] To a solution of B1-2-2 (1 equivalent, 1.72 g, 8.99 mmol), di(n-butyl)tin oxide (0.1 equivalent, 0.224 g, 0.899 mmol), and TBAB (0.3 equivalents, 0.870 g, 2.70 mmol), DIPEA (2 equivalents, 3.13 mL, 18.0 mmol) and BnBr (2 equivalents, 2.15 mL, 18.0 mmol) were added under an argon atmosphere at room temperature. The reaction mixture was stirred at 70°C for 6 hours. The reaction mixture was concentrated under reduced pressure, then placed in siRNA (50 mL), and filtered through a silica gel pad. The latter was rinsed with siRNA (3 × 150 mL), and the filtrate was concentrated under reduced pressure. The resulting orange oil (4.46 g) was purified by silica gel flash chromatography (120 g, gradient: cyclohexane / siRNA 100:0~50:50) to obtain a pale yellow oil containing other -OBn region isomers protected at position 2. 1 ¹H NMR analysis yielded B1-2-3 (2.31 g, 75%) contaminated with 17 wt%).

[0377] LC / MS (AN01_001_012): Rt=2.28 min, 100%, [M+Na] + =304.1.

[0378] tert-butyl(2S)-2-[(benzyloxy)methyl]-6-methylidene-1,4-oxazepane-4-carboxylate B1-2-13 [ka] To a suspension of 60% NaH (2.1 equivalents, 3.40 g, 85.1 mmol) in oil in anhydrous DMF (72 mL), 3-chloro-2-chloromethyl-1-propene (1 equivalent, 4.69 mL, 40.5 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 10 minutes, and a solution of B1-2-3 (1 equivalent, 11.4 g, 40.5 mmol) in anhydrous THF (50 mL) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water (200 mL), and the aqueous layer was extracted with ELISA (3 × 200 mL). The combined organic layers were washed with brine (200 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (330 g, gradient: cyclohexane / siRNA 100:0 to 90:10) to obtain B1-2-13 (5.93 g, 44%) as a colorless oil.

[0379] LC / MS (AN01_001_012): Rt=2.73 min, 100%, [M-C4H8+H] + = 278.1.

[0380] tert-butyl(2S)-2-[(benzyloxy)methyl]-6-oxo-1,4-oxazepan-4-carboxylate B1-2-14 [ka] To a solution of B1-2-13 (1 equivalent, 2.10 g, 6.30 mmol) in a mixture of DCM (38 mL) and acetonitrile (38 mL), 2,6-lutidine (2 equivalents, 1.47 mL, 12.6 mmol), water (57 mL), and sodium periodate (4 equivalents, 5.39 g, 25.2 mmol) were added at room temperature. A solution of RuCl3.3H2O (0.035 equivalents, 57.6 mg, 0.220 mmol) in water (6.3 mL) was added dropwise to form a brown suspension. The reaction mixture was vigorously stirred at room temperature for 2 hours. The reaction mixture was diluted with water (150 mL) and extracted with DCM (3 × 150 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (120 g, gradient: 100:0~85:15 cyclohexane / toluene) to obtain B1-2-14 (1.88 g, 89%) as a colorless oil.

[0381] LC / MS(AN01_001_012): Rt=2.56 min, 100%, [M+H] + = 336.1.

[0382] tert-butyl(2S,6S*)-2-[(benzyloxy)methyl]-6-hydroxy-6-methyl-1,4-oxazepane-4-carboxylate B1-46-1-(S)* and tert-butyl(2S,6R*)-2-[(benzyloxy)methyl]-6-hydroxy-6-methyl-1,4-oxazepane-4-carboxylate B1-46-1-(R)* [ka] To a solution of B1-2-14 (1 equivalent, 1.28 g, 3.82 mmol) in anhydrous THF (35 mL), a 3 M solution of MeMgBr in Et2O (2.5 equivalents, 3.18 mL, 9.54 mmol) was added under an argon atmosphere at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with a saturated aqueous solution of NH4Cl (100 mL), and the aqueous layer was extracted with siRNA (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (80 g, gradient: 100:0 to 70:30 cyclohexane / siRNA) to obtain B1-46-1-(S)* (0.650 g, 48%) and B1-46-1-(R)* (0.363 g, 27%) as colorless oils. The stereochemistry (S)* was assigned to the first elution product by flash chromatography, and then the second elution product was assigned to (R)*. B1-46-1-(S)*:LC / MS(AN01_001_012):Rt=2.47 min, 100%, [M-C4H8+H] + = 296.2. B1-46-1-(R)*:LC / MS(AN01_001_012):Rt=2.41 min, 100%, [M-C4H8+H] + = 296.2.

[0383] Example 2. Synthesis of B1-46-3-(R)* and B1-46-5-(S)* Synthetic scheme for the preparation of compound 2-A: Protecting group-free approach (A) [ka] tert-butyl(2S,6R*)-6-hydroxy-2-(hydroxymethyl)-6-methyl-1,4-oxazepan-4-carboxylate B1-46-2-(R)* [ka] Starting with B1-46-1-(R)* (1 equivalent, 0.160 g, 0.455 mmol), B1-46-2-(R)* (0.119 g, 100%) was obtained as a colorless oil using general procedure A.

[0384] LC / MS (AN01_001_012): Rt=1.83 min, non-UV active, [M+Na] + = 284.1.

[0385] (2S,6R*)-4-[(tert-butoxy)carbonyl]-6-hydroxy-6-methyl-1,4-oxazepan-2-carboxylic acid B1-46-3-(R)* [ka] A solution of B1-46-2-(R)* (1 equivalent, 0.110 g, 0.421 mmol) and sodium bromide (0.3 equivalents, 13.2 mg, 0.126 mmol) in acetone (7 mL) was mixed with a saturated aqueous solution of NaHCO3 (2 mL) at room temperature. Trichlorocyanuric acid (2.2 equivalents, 0.215 mg, 0.926 mmol) and 2,2,6,6-tetramethylpiperidine-1-oxyl (0.03 equivalents, 1.97 mg, 0.0126 mmol) were added to the resulting mixture at 0°C. The reaction mixture was warmed to room temperature and stirred for 18 hours. Isopropanol (10 mL) was added at room temperature, and the reaction mixture was stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate (50 mL), and a saturated aqueous solution of NaHCO3 (50 mL) was added. The two layers were separated, and the aqueous layer was washed with ethyl acetate (50 mL). Next, the aqueous layer was acidified to approximately pH 1 with a 3M HCl aqueous solution and extracted with DCM (2 × 50 mL). The aqueous layer was further extracted with a mixture of CHCl3 / isopropanol (8:2, 2 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain B1-46-3-(R)* (42.6 mg, 37%) as a yellowish oil.

[0386] LC / MS (AN01_001_012): Rt=1.83 min, non-UV active, [M+Na] + = 298.1.

[0387] Synthetic scheme for the preparation of compound 2-B: Protecting group approach (B) [ka] (2S,6S*)-2-[(benzyloxy)methyl]-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepane B1-46-2-(S)* [ka] To a solution of B1-46-1-(S)* (1 equivalent, 0.320 g, 0.911 mmol) and 2,6-lutidine (2.5 equivalents, 0.265 mL, 2.28 mmol) in anhydrous DCM (3 mL), TBDMSOTf (1.5 equivalents, 0.310 mL, 1.37 mmol) and DMAP (0.05 equivalents, 5.56 mg, 0.0455 mmol) were added under an argon atmosphere. The reaction mixture was stirred at room temperature for 6 hours. The resulting mixture was diluted with DCM (50 mL) and water (50 mL). The two layers were separated, and the aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (40 g, gradient: cyclohexane / siRNA, 100 / 0~50:50) to obtain B1-46-2-(S)* (0.308 g, 93%) as a pale yellow oil.

[0388] LC / MS (AN01_001_012): Rt=2.30 min, 100%, [M+H] + = 366.3.

[0389] tert-butyl(2S,6S*)-2-[(benzyloxy)methyl]-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepane-4-carboxylate B1-46-3-(S)* [ka] A solution of B1-46-2-(S)* (1 equivalent, 0.305 g, 0.834 mmol) and Et3N (1.01 equivalents, 0.117 mL, 0.843 mmol) in anhydrous MeOH (1.3 mL) was then mixed with a solution of Boc2O (1.2 equivalents, 0.218 g, 1.00 mmol) in anhydrous DCM (0.25 mL) under an argon atmosphere. The reaction mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure to obtain B1-46-3-(S)* (0.389 g, quantitative) as a colorless oil. The crude mixture was considered quantitative and used as is.

[0390] LC / MS (AN01_001_012): Rt=3.38 min, 100%, [M+Na] + = 488.3.

[0391] tert-butyl(2S,6S*)-6-[(tert-butyldimethylsilyl)oxy]-2-(hydroxymethyl)-6-methyl-1,4-oxazepane-4-carboxylate B1-46-4-(S)* [ka] Starting with B1-46-3-(S)* (1 equivalent, 0.385 g, 0.827 mmol), B1-46-4-(S)* (0.306 g, 99%) was obtained as a colorless oil using general procedure A.

[0392] LC / MS (AN01_001_012): Rt = 2.95 min, no UV activity, [M-C4H8+H] + = 320.2.

[0393] (2S,6S*)-4-[(tert-butoxy)carbonyl]-6-[(tert-butyldimethylsilyl)oxy]-6-methyl-1,4-oxazepan-2-carboxylic acid B1-46-5-(S)* [ka] Starting with B1-46-4-(S)* (1 equivalent, 0.290 g, 0.772 mmol), B1-46-5-(S)* (0.219 g, 73%) was obtained as a yellowish oil using general procedure B.

[0394] LC / MS (AN01_001_012): Rt = 2.84 mins, no UV activity, [M+Na] + = 412.2.

[0395] Example 3: Synthesis of B1-47-3-(S)* and B1-47-3-(R)* [ka] tert-butyl(2S,6S*)-2-[(benzyloxy)methyl]-6-methoxy-6-methyl-1,4-oxazepane-4-carboxylate B1-47-1-(S)* [ka] Starting with B1-46-1-(S)* (1 equivalent, 0.320 g, 0.910 mmol), the following procedure E was used to purify the substance by silica gel flash chromatography (25 g, gradient: cyclohexane / siRNA 100:0~80:20) to obtain B1-47-1-(S)* (0.268 g, 81%) as a colorless oil.

[0396] LC / MS (AN01_001_012): Rt=2.65 min, 100%, [M+Na]+=388.2.

[0397] tert-butyl(2S,6S*)-2-(hydroxymethyl)-6-methoxy-6-methyl-1,4-oxazepane-4-carboxylate B1-47-2-(S)* [ka] Starting with B1-47-1-(S)* (1 equivalent, 0.265 g, 0.725 mmol), B1-47-2-(S)* (0.181 g, 91%) was obtained as a colorless oil using general procedure A.

[0398] LC / MS (AN01_001_012): Rt=2.00 min, non-UV active, [M+Na] + = 298.2.

[0399] (2S,6S*)-4-[(tert-butoxy)carbonyl]-6-methoxy-6-methyl-1,4-oxazepan-2-carboxylic acid B1-47-3-(S)* [ka] Starting with B1-47-2-(S)* (1 equivalent, 0.175 g, 0.636 mmol), B1-47-3-(S)* (0.147 g, 80%) was obtained as a white solid using general procedure B.

[0400] LC / MS (AN01_001_012): Rt=1.98 min, non-UV active, [M+Na] + = 312.1. [ka]

[0401] tert-butyl(2S,6R*)-2-[(benzyloxy)methyl]-6-methoxy-6-methyl-1,4-oxazepane-4-carboxylate B1-47-1-(R)* [ka] Starting with B1-46-1-(R)* (1 equivalent, 0.360 g, 1.02 mmol), the following purification was performed using general procedure E by silica gel flash chromatography (25 g, gradient: cyclohexane / dimethyl 100:0~75:25) to obtain B1-47-1-(R)* (0.311 g, 83%) as a colorless oil.

[0402] LC / MS (AN01_001_012): Rt=2.65 min, 100%, [M+Na] + = 388.2.

[0403] tert-butyl(2S,6R*)-2-(hydroxymethyl)-6-methoxy-6-methyl-1,4-oxazepane-4-carboxylate B1-47-2-(R)* [ka] Starting with B1-47-1-(R)* (1 equivalent, 0.310 g, 0.848 mmol), B1-47-2-(R)* (0.208 g, 89%) was obtained as a colorless oil using general procedure A.

[0404] LC / MS (AN01_001_012): Rt=2.00 min, non-UV active, [M+Na] + = 298.1.

[0405] (2S,6R*)-4-[(tert-butoxy)carbonyl]-6-methoxy-6-methyl-1,4-oxazepan-2-carboxylic acid B1-47-3-(R)* [ka] Starting with B1-47-2-(R)* (1 equivalent, 0.205 g, 0.744 mmol), B1-47-3-(R)* (0.124 g, 58%) was obtained as a white solid using general procedure B.

[0406] LC / MS (AN01_001_012): Rt=2.00 min, non-UV active, [M+Na] + = 312.1.

[0407] Example 4: Synthesis of H1-2-7 [ka] Ethyl 3-[(buta-3-en-1-yl)[(tert-butoxy)carbonyl]amino]propanoate H1-2-3 [ka] Argon-purged solutions of buta-3-en-1-amine hydrochloride H1-2-1 (1 equivalent, 1.99 g, 18.5 mmol) and triethylamine (1.05 equivalents, 2.70 mL, 19.4 mmol) in EtOH (28 mL) were stirred at room temperature for 30 minutes. Then, ethyl acrylate (1 equivalent, 2.01 mL, 18.5 mmol) was added, and the resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude mixture (4.88 g, estimated purity: 50%) containing H1-2-2 as a colorless oil.

[0408] To an argon-purged solution of a crude mixture containing H1-2-2 in DCM (30 mL) (4.88 g, estimated purity: 50%, 14.2 mmol, 1 equivalent), diisopropylamine (1.2 equivalents, 2.42 mL, 17.1 mmol), Boc2O (1.2 equivalents, 3.73 g, 17.1 mmol), and DMAP (0.1 equivalent, 0.170 g, 1.42 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 19 hours. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting yellow oil was purified twice by silica gel flash chromatography (first flash chromatography: 120 g, gradient: 100:0~80:20 cyclohexane / siRNA; second flash chromatography: 40 g, gradient: 80:20~0:100 cyclohexane / DCM, followed by 100:0~80:20 DCM / EtOAC) to obtain H1-2-3 (1.99 g, 40% over two steps) as a colorless oil.

[0409] LC / MS (AN01_001_012): Rt=2.65 min, 100%, [M-C4H8+H] + = 216.2.

[0410] Ethyl 2-{[(buta-3-en-1-yl)[(tert-butoxy)carbonyl]amino]methyl}pent-4-enoate H1-2-4 [ka] To an argon-purged solution of H1-2-3 (1 equivalent, 1.99 g, 7.33 mmol) in THF (20 mL), a 1 M LiHMDS solution in THF (1.1 equivalents, 8.07 mL, 8.07 mmol) was added dropwise at -78°C. The resulting mixture was stirred at -78°C for 1 hour, after which allyl iodide (1.1 equivalents, 0.740 mL, 8.07 mmol) was added dropwise. The resulting mixture was warmed to room temperature and stirred for 15 hours. The reaction mixture was cooled to -78°C, and a 1 M LiHMDS solution in THF (0.2 equivalents, 1.47 mL, 1.47 mmol) was added dropwise at -78°C. The reaction mixture was stirred at this temperature for 30 minutes, after which allyl iodide (0.2 equivalents, 0.135 mL, 1.47 mmol) was added dropwise. The resulting mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was diluted with water (100 mL) and extracted with siRNA (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting orange oil was purified by silica gel flash chromatography (80 g, gradient: 100:0 to 80:20 cyclohexane / siRNA) to obtain H₁-2-4 (1.62 g, 71%) as a yellow oil.

[0411] LC / MS(AN01_001_012): Rt=2.85 min, 100%, [M-C5H8O2+H] + = 212.2.

[0412] 1-tert-butyl 3-ethyl 1,2,3,4,7,8-hexahydroazosin-1,3-dicarboxylate H1-2-5 [ka] To an argon-purged solution of H1-2-4 (1 equivalent, 1.20 g, 3.85 mmol) in DCM (200 mL), benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (0.1 equivalent, 0.318 g, 0.385 mmol) was added at room temperature. The resulting mixture was stirred and refluxed for 7 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting black oil was purified by silica gel flash chromatography (80 g, gradient: 100:0 to 80:20 cyclohexane / siRNA) to obtain H1-2-5 (0.613 g, 56%) as black oil.

[0413] LC / MS(AN01_001_012): Rt=2.67 min, 81%, [M-C4H8+H] + = 228.1.

[0414] 1-tert-butyl 3-ethylazocan-1,3-dicarboxylate H1-2-6 [ka] To an argon-purged solution of H1-2-5 (1 equivalent, 0.350 g, 1.24 mmol) in EtOH (6 mL), 10% Pd / C (0.2 equivalents, 0.263 g, 0.247 mmol) was added at room temperature. The resulting mixture was purged with argon (3 times) and then with H2 (3 times). The reaction mixture was stirred at room temperature under atmospheric pressure of H2 for 19 hours. The reaction mixture was purged with argon, filtered through a Celite pad, and rinsed with EtOH (2 × 15 mL). The filtrate was concentrated under reduced pressure to obtain H1-2-6 (0.323 g, 92%) as a yellow oil.

[0415] LC / MS (AN01_001_012): Rt=2.73 min, non-UV active, [M-C4H8+H] + = 230.1.

[0416] 1-[(tert-butoxy)carbonyl]azocane-3-carboxylic acid H1-2-7 [ka] A solution of H1-2-6 (1 equivalent, 0.323 g, 1.13 mmol) in THF (11 mL) was mixed with a solution of LiOH (5 equivalents, 0.237 g, 5.66 mmol) in water (5.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 19 hours. The reaction mixture was poured into a stirred mixture of 1 M aqueous HCl (50 mL) and DCM (100 mL) and added dropwise at 0°C. The resulting mixture was stirred for 1 hour (pH approximately 1), and the layers were separated. The aqueous layer was extracted with DCM (2 × 50 mL), the combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain H1-2-7 (0.291 g, 100%) as a yellow oil.

[0417] LC / MS (AN01_001_012): Rt=2.29 min, non-UV active, [M+Na] + = 280.2.

[0418] Example 5. General scheme for the synthesis of (S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)bicyclo[2.2.2]octan-1-yl)ethyl)-1,4-oxazepan-2-carboxamide (S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)bicyclo[2.2.2]octan-1-yl)ethyl)-1,4-oxazepan-2-carboxamide can be prepared according to the following scheme. [ka]

[0419] Example 6. General scheme for the synthesis of (2S)-N-(1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)benzo[b]thiophen-2-yl)ethyl)-1,4-oxazepan-2-carboxamide (2S)-N-(1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)benzo[b]thiophen-2-yl)ethyl)-1,4-oxazepan-2-carboxamide can be prepared according to the following scheme. [ka]

[0420] Example 7. General scheme for the synthesis of (2S)-N-(1-cyano-2-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)benzo[b]thiophene-6-yl)ethyl)-1,4-oxazepan-2-carboxamide (2S)-N-(1-cyano-2-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)benzo[b]thiophen-6-yl)ethyl)-1,4-oxazepan-2-carboxamide can be prepared according to the following scheme. [ka]

[0421] Example 8: IC50 assay Mouse DPP1 enzyme IC50 assay The test substance is applied to active mouse DPP1 enzyme (R&D Systems, Minneapolis, MN) in assay buffer (50 mM MES, pH 5.5, 50 mM NaCl, 5 mM DTT) in a total reaction volume of 125 μL. 25 μL of the compound + 5% DMSO in the assay buffer is first added to 50 μL of active mouse DPP1 enzyme at a concentration of 62.5 pg / μL, pre-incubated at 37°C for 10 minutes, and then 50 μL of 1000 μM H-Gly-Arg-AMC substrate (Bachem, St. Torrance, CA) is added to obtain a final substrate concentration of 400 μM and a final DMSO concentration of 1%. Substrate cleavage is measured at 37°C for 90 minutes, and fluorescence at excitation / emission 350 / 450 nm is measured every 5 minutes. The DPP1 concentration is interpolated based on its activity relative to the standard curve of recombinant active mouse DPP1 enzyme. The IC50 values ​​for each compound are calculated using XLFit (IDBS version 5.3.1.3). The 4-parameter fit formula y=(A+((BA) / (1+((C / x)^D)))) is used as an add-on to Microsoft Excel, which appears in XLFit as formula number 205 (4-parameter logistic model or sigmoid dose-response model). Default constraints are used for each parameter. IC50 is defined as the compound concentration at which 50% of enzyme activity is inhibited compared to a non-compound control.

[0422] Human DPP1 Enzyme IC50 Assay Recombinant human DPP1 enzyme (R&D Systems, Minneapolis, MN) is first proteolytically treated to its mature form using recombinant human cathepsin L (R&D Systems) in a buffer consisting of 20 mM citrate pH 4.5, 150 mM NaCl, 1 mM EDTA, and 10 mM DTT. The test substance is then applied to the activated human DPP1 enzyme in assay buffer (25 mM MES pH 6.0, 50 mM NaCl, 5 mM DTT) with a total reaction volume of 125 μL. First, 25 μL of the compound + 5% DMSO in the assay buffer was added to 50 μL of activated human DPP1 enzyme at a concentration of 1 ng / μL, pre-incubated at 37°C for 10 minutes, and then 50 μL of 1000 μM H-Gly-Arg-AMC substrate (Bachem; St. Torrance, CA) was added to obtain a final substrate concentration of 400 μM and a final DMSO concentration of 1%. Substrate cleavage was measured at 37°C for 90 minutes, and fluorescence at excitation / emission 350 / 450 nm was measured every 5 minutes. The DPP1 concentration was interpolated based on its activity relative to the standard curve of activated human recombinant DPP1 enzyme. The IC50 value of each compound was calculated by XLFit (IDBS version 5.3.1.3). The 4-parameter fitting formula y={A+[(BA)] / [1+((C / x)^D)]} is used as an add-on to Microsoft Excel, and this appears in XLFit as formula number 205 (4-parameter logistic model or sigmoid dose-response model). Default constraints are used for each parameter. IC50 is defined as the compound concentration at which 50% of the enzyme activity is inhibited compared to a non-compound control. The IC50 table is included in the table below. [Table 2]

[0423] Example 9. Synthesis of Compound 112a: (2S)-N-{1-cyano-2-[2-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophen-6-yl]ethyl}-1,4-oxazepan-2-carboxamide [ka] Synthesis of methyl 2-bromo-1-benzothiophene-6-carboxylate [ka] To a stirred solution of methyl 1-benzothiophene-6-carboxylate (2 g, 10.404 mmol, 1 equivalent) and THF (30 mL), LDA (2 M in THF) (6.24 mL, 12.49 mmol, 1.2 equivalents) was added dropwise at -78°C under a nitrogen atmosphere. The resulting mixture was stirred at -78°C under a nitrogen atmosphere for 1 hour. Dibromoethane (2.15 g, 11.44 mmol, 1.1 equivalents) was added dropwise to the above mixture at -78°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for a further 1 hour. The reaction was quenched by adding water (50 mL) at room temperature. The resulting mixture was extracted with SiO2 (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA (12:1) elution to obtain methyl 2-bromo-1-benzothiophene-6-carboxylate (1.7 g, 60.26%) as a pale yellow oil. (No MS signal was observed on LCMS.) 1 H NMR(300MHz,DMSO-d6) δ 8.63(dt,J=1.6,0.8Hz,1H),7.95(dd,J=8.4,1.4Hz,1H),7.91(dd,J=8.3,0.8Hz,1H),7.77(d,J=0.7Hz,1H),3.89(s,3H).

[0424] Synthesis of (2-bromo-1-benzothiophen-6-yl)methanol [ka] A solution of methyl 2-bromo-1-benzothiophene-6-carboxylate (0.9 g, 3.32 mmol, 1 equivalent) and DIBAL-H (9.96 mL, 9.96 mmol, 3 equivalents) in tetrahydrofuran (40 mL, 14.38 mmol) was stirred under a nitrogen atmosphere from -78°C to room temperature for 2 hours. The reaction mixture was quenched with HCl (1 M) at 0°C. The resulting mixture was extracted with RINKAN (3 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried on anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to obtain (2-bromo-1-benzothiophene-6-yl)methanol (0.65 g, 80.54%) as a white solid. LCMS(ES, m / z):[M-18+H] + :225 1 H NMR(300MHz,DMSO-d6) δ 7.86(s,1H),7.75(d,J=8.2Hz,1H),7.61(s,1H),7.34(dd,J=8.2,1.5Hz,1H),5.30(t,J=5.7Hz,1H),4.59(d,J=5.7Hz,2H).

[0425] Synthesis of 2-bromo-6-(bromomethyl)-1-benzothiophene [ka] To a solution of (2-bromo-1-benzothiophen-6-yl)methanol (0.65 g, 2.674 mmol, 1 equivalent) in Et2O (10 mL), PBr3 (0.36 g, 1.337 mmol, 0.5 equivalent) was added at 0°C. The resulting mixture was stirred at room temperature for a further 2 hours. The reaction was quenched by adding water at 0°C. The resulting mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried on anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded 2-bromo-6-(bromomethyl)-1-benzothiophene (700 mg, 85.56%) as a white solid. (No MS signal on LCMS) 1H NMR(300MHz,DMSO-d6) δ 8.05(d,J=1.6Hz,1H),7.80(d,J=8.2Hz,1H),7.66(s,1H),7.46(dd,J=8.2,1.7Hz,1H),4.83(s,2H).

[0426] Synthesis of 3-(2-bromo-1-benzothiophen-6-yl)-2-[(diphenylmethylidene)amino]propanenitrile [ka] A solution of 2-bromo-6-(bromomethyl)-1-benzothiophene (600 mg, 1.96 mmol, 1.0 equivalent) in DCM (5 mL) was mixed with 2-[(diphenylmethylidene)amino]acetonitrile (432 mg, 1.96 mmol, 1.0 equivalent), benzyltrimethylazanium chloride (36.41 mg, 0.196 mmol, 0.1 equivalent), and NaOH (156 mg, 3.92 mmol, 2.0 equivalent) in H2O (1 mL) and stirred at 40°C for 36 hours. The resulting mixture was extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / THF (5:1) to obtain 3-(2-bromo-1-benzothiophen-6-yl)-2-[(diphenylmethylidene)amino]propanenitrile (800 mg crude product) as a yellow solid. LCMS(ES,m / z):[M+H] + :445.

[0427] Synthesis of 2-[(diphenylmethylidene)amino]-3-[2-(3-methyl-2-oxo-1,3-benzoxazole-6-yl)-1-benzothiophen-5-yl]propanenitrile [ka] A solution of 1,4-dioxane (10 mL) with 3-(2-bromo-1-benzothiophen-6-yl)-2-[(diphenylmethylidene)amino]propanenitrile (800 mg, 1.80 mmol, 1.0 equivalent), 3-methyl-5-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazole-2-one (468 mg, 1.80 mmol, 1.0 equivalent), K2CO3 (496 mg, 3.59 mmol, 2.0 equivalent), and Pd(dppf)Cl2 (131 mg, 0.18 mmol, 0.1 equivalent) was mixed with H2O (1 mL) and stirred at 80°C for 2 hours under a nitrogen atmosphere. The residue was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / THF (5:1) to obtain 2-[(diphenylmethylidene)amino]-3-[2-(3-methyl-2-oxo-1,3-benzoxazole-6-yl)-1-benzothiophene-5-yl]propanenitrile (600 mg, 65.04%) as a white solid. LCMS(ES,m / z):[M+H] + :514.

[0428] Synthesis of 2-amino-3-[2-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-6-yl]propanenitrile [ka] 600 mg (1.17 mmol, 1 equivalent) of 2-[(diphenylmethylidene)amino]-3-[2-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophene-6-yl]propanenitrile, 50 mL of THF, and 5 mL of H2O were added to a 100 mL round-bottom flask at room temperature. The resulting mixture was stirred at room temperature for a further 3 hours. The mixture was basicized to pH 12 with NaOH. The resulting mixture was extracted with ELISA (3 × 50 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / THF (2:1) to obtain 2-amino-3-[2-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophene-6-yl]propanenitrile (300 mg, 73.50%) as a white solid. LCMS(ES,m / z):[M+H] + :350.

[0429] Synthesis of tert-butyl(2S)-2-({1-cyano-2-[2-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophen-6-yl]ethyl}carbamoyl)-1,4-oxazepan-4-carboxylate [ka] HATU (120 mg, 0.32 mmol, 1.2 equivalents) was added at 0°C to a stirred mixture of 2-amino-3-[2-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophene-6-yl]propanenitrile (110 mg, 0.32 mmol, 1.2 equivalents), (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepan-2-carboxylic acid (64 mg, 0.26 mmol, 1.0 equivalent), and DIEA (102 mg, 0.79 mmol, 3.0 equivalents) in DCM (5 mL). The resulting mixture was further stirred at 0°C for 2 hours. The residue was purified by silica gel column chromatography eluting with PE / THF (1:1) to obtain tert-butyl(2S)-2-({1-cyano-2-[2-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-6-yl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate (120 mg, 79.32%) as a pale yellow oil. LCMS(ES,m / z):[M+H] + :577.

[0430] Synthesis of (2S)-N-{1-cyano-2-[2-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-6-yl]ethyl}-1,4-oxazepan-2-carboxamide [ka] In a 50 mL round-bottom flask, tert-butyl(2S)-2-({1-cyano-2-[2-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-6-yl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate (120 mg, 0.21 mmol, 1 equivalent), TsOH (108 mg, 0.62 mmol, 3.0 equivalents), and ACN (3 mL) were added at room temperature. The resulting mixture was stirred at room temperature for a further 3 hours. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH3, H2O) in water, gradient from 10% to 50% over 10 minutes; detector, UV 254 nm. This yielded (2S)-N-{1-cyano-2-[2-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophene-6-yl]ethyl}-1,4-oxazepan-2-carboxamide (18.5 mg, 18.66%) as a white solid. Analysis data LCMS(ES,m / z):[M+H] + :477. 1 H NMR(400MHz,DMSO-d6) δ 8.62(dd,J=11.8,8.5Hz,1H),7.91-7.84(m,2H),7.79(dd,J=8.2,2.9Hz,1H),7.73(d,J=1.9Hz, 1H),7.51(dt,J=8.3,2.0Hz,1H),7.42(d,J=8.3Hz,1H),7.33(dt,J=8.1,1.7Hz,1H),5.13-4.93 (m,1H),4.01-3.80(m,2H),3.78-3.65(m,1H),3.43(s,3H),3.30-3.27(m,2H),3.05(ddd,J=52. 3,14.2,3.7Hz,1H),2.84-2.63(m,2H),2.60-2.53(m,1H),2.49-2.41(m,1H),1.79-1.65(m,2H).

[0431] Example 10. Synthesis of Compound 113a: (2S)-N-(1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)benzo[b]thiophen-2-yl)ethyl)-1,4-oxazepan-2-carboxamide [ka] Synthesis of (6-bromo-1-benzothiophen-2-yl)methanol [ka] To a solution of methyl 6-bromo-1-benzothiophene-2-carboxylate (4.0 g, 14.75 mmol, 1.0 equivalent) in MeOH (30.0 mL) and THF (60.0 mL), NaBH4 (1.1 g, 29.50 mmol, 2.0 equivalents) was added at 0°C. The mixture was stirred at 0°C for 16 hours. The reaction product was quenched with water (100 mL) and extracted with siRNA (3 × 100 mL). The combined organic layer was washed with brine (3 × 30 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / THF (5:1) to obtain (6-bromo-1-benzothiophene-2-yl)methanol (3.3 g, 92%) as a yellow-green solid. LCMS(ES, m / z):[M+H] + :243.

[0432] Synthesis of 6-bromo-2-(bromomethyl)-1-benzothiophene [ka] To a solution of (6-bromo-1-benzothiophen-2-yl)methanol (2.0 g, 8.22 mmol, 1.0 equivalent) in DCM (40 mL), NBS (1.8 g, 9.87 mmol, 1.2 equivalents) and PPh3 (2.6 g, 9.87 mmol, 1.2 equivalents) were added sequentially. The mixture was stirred at room temperature for 2 hours. The solution was concentrated to remove the solvent, and the residue was purified by silica gel column chromatography eluting with PE / EA (20:1) to obtain 6-bromo-2-(bromomethyl)-1-benzothiophene (2.3 g, 91%) as a yellow-green solid. LCMS(ES, m / z):[M+H] + :305.

[0433] Synthesis of 3-(6-bromo-1-benzothiophen-2-yl)-2-[(diphenylmethylidene)amino]propanenitrile [ka] A solution of 6-bromo-2-(bromomethyl)-1-benzothiophene (2.3 g, 7.51 mmol, 1.0 equivalent) in DCM (20 mL) was mixed with 2-[(diphenylmethylidene)amino]acetonitrile (1.7 g, 7.53 mmol, 1.0 equivalent), benzyltrimethylazanium chloride (0.1 g, 0.75 mmol, 0.1 equivalent), and NaOH (0.6 g, 15.03 mmol, 2.0 equivalent) in H2O (2 mL) and stirred at 40°C for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with CH2Cl2 (3 × 100 mL). The combined organic layer was washed with brine (3 × 30 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / THF (5:1) to obtain 3-(6-bromo-1-benzothiophen-2-yl)-2-[(diphenylmethylidene)amino]propanenitrile (1.3 g, 39%) as a white solid. LCMS(ES, m / z):[M+H] + :445.

[0434] Synthesis of 2-[(diphenylmethylidene)amino]-3-[6-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]propanenitrile [ka] To a solution of 3-(6-bromo-1-benzothiophen-2-yl)-2-[(diphenylmethylidene)amino]propanenitrile (700 mg, 1.57 mmol, 1.0 equivalent) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazole-2-one (518 mg, 1.88 mmol, 1.2 equivalents) in 1,4-dioxane (10 mL) and H2O (1 mL), K2CO3 (434 mg, 3.14 mmol, 2.0 equivalents) and Pd(dppf)Cl2 (115 mg, 0.15 mmol, 0.1 equivalent) were added sequentially. The mixture was stirred at 90°C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated, and the solvent removed. The residue was purified by silica gel column chromatography eluting with PE / THF (1:1) to obtain 2-[(diphenylmethylidene)amino]-3-[6-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]propanenitrile (800 mg, 99%) as a yellow oil. LCMS(ES,m / z):[M+H] + :514.

[0435] Synthesis of 2-amino-3-[6-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]propanenitrile [ka] In a 100 mL round-bottom flask, 2-[(diphenylmethylidene)amino]-3-[6-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]propanenitrile (400 mg, 0.77 mmol, 1.0 equivalent), THF (25 mL), H2O (2.5 mL), and HCl (1 M) (1 mL) were added sequentially at room temperature. The resulting mixture was stirred at room temperature for a further 3 hours. The reaction product was diluted with water (50 mL) and extracted with Et2O (50 mL). The aqueous phase was basicized to pH=8 with Na2CO3 solid and extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded 2-amino-3-[6-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophene-2-yl]propanenitrile (140 mg, 51%) as a white solid. LCMS(ES,m / z):[M+H] + :350.

[0436] Synthesis of tert-butyl(2S)-2-({1-cyano-2-[6-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophen-2-yl]ethyl}carbamoyl)-1,4-oxazepan-4-carboxylate [ka] A solution of 2-amino-3-[6-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]propanenitrile (140 mg, 0.40 mmol, 1.2 equivalents) in DCM (5 mL) was treated with (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepan-2-carboxylic acid (82 mg, 0.33 mmol, 1.0 equivalent) and DIEA (129 mg, 1.00 mmol, 3.0 equivalents), followed by the addition of HATU (152 mg, 0.40 mmol, 1.2 equivalents) in several portions at 0°C. The resulting mixture was further stirred at 0°C for 3 hours. The solution was concentrated, the solvent was removed, and the residue was purified by silica gel column chromatography eluted with PE / THF (1:1) to obtain tert-butyl(2S)-2-({1-cyano-2-[6-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]ethyl}carbamoyl)-1,4-oxazepan-4-carboxylate (190 mg, 98%) as a white solid. LCMS(ES,m / z):[M+H] + :577.

[0437] Synthesis of (2S)-N-(1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)benzo[b]thiophen-2-yl)ethyl)-1,4-oxazepan-2-carboxamide [ka] In a 50 mL round-bottom flask, tert-butyl(2S)-2-({1-cyano-2-[6-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate (100 mg, 0.17 mmol, 1.0 equivalent), TsOH (90 mg, 0.51 mmol, 3.0 equivalents), and ACN (3 mL) were added at room temperature. The resulting mixture was stirred at room temperature for a further 3 hours. The reaction solution was purified by reverse-phase flash chromatography under the following conditions: column, C18-120 g; mobile phase, MeCN in water (0.1% NH3, H2O), 10% to 80% gradient over 10 mins; detector, UV 254 nm. The fraction was freeze-dried to obtain (2S)-N-(1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)benzo[b]thiophen-2-yl)ethyl)-1,4-oxazepan-2-carboxamide (16.3 mg, 20%) as a white solid. Analysis data LCMS(ES,m / z):[M+H] + :477. 1 H NMR(400MHz,DMSO-d6) δ 8.74(d,J=8.2Hz,1H),8.28(s,1H),7.88(dd,J=8.3,2.5Hz,1H),7.72(d,J=8.3Hz,1H ),7.69(d,J=1.8Hz,1H),7.51(dd,J=8.7,1.7Hz,1H),7.42(d,J=8.3Hz,1H),7.35(s, 1H),5.14-5.04(m,1H),4.07-3.95(m,1H),3.95-3.83(m,1H),3.77-3.72(m,1H),3.5 9-3.51(m,2H),3.43(s,3H),3.20-3.03(m,1H),2.88-2.59(m,3H),1.81-1.72(m,2H).

[0438] Example 11. Synthesis of Compound 114a: (2S)-N-{1-cyano-2-[5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophen-2-yl]ethyl}-1,4-oxazepan-2-carboxamide [ka] Synthesis of (5-bromo-1-benzothiophen-2-yl)methanol [ka] A solution of methyl 5-bromo-1-benzothiophene-2-carboxylate (3.0 g, 11.06 mmol, 1.0 equivalent) and NaBH4 (0.84 g, 22.130 mmol, 2.0 equivalents) in MeOH (20 mL) and THF (40 mL) was stirred at 0°C for 16 hours. The resulting mixture was extracted with ELISA (3 × 100 mL). The combined organic layer was washed with brine (3 × 30 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / THF (5:1) to obtain (5-bromo-1-benzothiophene-2-yl)methanol (2.7 g, crude product) as a yellow-green solid. 1 H NMR(300MHz,DMSO-d6) δ 8.01(d,J=2.0Hz,1H),7.90(d,J=8.5Hz,1H),7.44(dd,J=8.5,2.0Hz,1H),7.25(q,J=1.0Hz,1H),5.72(t,J=5.8Hz,1H),4.76(dd,J=5.8,1.2Hz,2H).

[0439] Synthesis of 5-bromo-2-(bromomethyl)-1-benzothiophene [ka] A solution of (5-bromo-1-benzothiophen-2-yl)methanol (2.0 g, 8.22 mmol, 1.0 equivalent), NBS (1.8 g, 9.87 mmol, 1.2 equivalents), and PPh3 (2.6 g, 9.87 mmol, 1.2 equivalents) in DCM (40 mL) was stirred at room temperature for 2 hours. The residue was purified by silica gel column chromatography eluted with PE / EA (20:1) to obtain 5-bromo-2-(bromomethyl)-1-benzothiophene (2.2 g, 87.3%) as a yellow-green solid.

[0440] Synthesis of 3-(5-bromo-1-benzothiophen-2-yl)-2-[(diphenylmethylidene)amino]propanenitrile [ka] A solution of 5-bromo-2-(bromomethyl)-1-benzothiophene (2.2 g, 7.18 mmol, 1.0 equivalent) in DCM (20 mL) was mixed with 2-[(diphenylmethylidene)amino]acetonitrile (1.6 g, 7.18 mmol, 1.0 equivalent), benzyltrimethylazanium chloride (0.1 g, 0.71 mmol, 0.1 equivalent), and NaOH (0.6 g, 14.37 mmol, 2.0 equivalent) in H2O (2 mL), and stirred at 40°C for 2 hours. The resulting mixture was extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / THF (5:1) to obtain 3-(5-bromo-1-benzothiophen-2-yl)-2-[(diphenylmethylidene)amino]propanenitrile (2.3 g, 71.8%) as a white solid. LCMS(ES, m / z):[M+H] + :445

[0441] Synthesis of 2-[(diphenylmethylidene)amino]-3-[5-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]propanenitrile [ka] A solution of 3-(5-bromo-1-benzothiophen-2-yl)-2-[(diphenylmethylidene)amino]propanenitrile (1.0 g, 2.24 mmol, 1.0 equivalent), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazole-2-one (0.7 g, 2.694 mmol, 1.2 equivalents), K2CO3 (0.6 g, 4.49 mmol, 2.0 equivalents), and Pd(dppf)Cl2 (0.2 g, 0.22 mmol, 0.1 equivalent) in 1,4-dioxane (10 mL) and H2O (1 mL) was stirred at 90°C for 2 hours under a nitrogen atmosphere. The residue was purified by silica gel column chromatography eluted with PE / THF (1:1) to obtain 2-[(diphenylmethylidene)amino]-3-[5-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophene-2-yl]propanenitrile (1.1 g, 95.3%) as a yellow solid. LCMS(ES,m / z):[M+H] + :514

[0442] Synthesis of 2-amino-3-[5-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]propanenitrile [ka] 500 mg (0.97 mmol, 1.0 equivalent) of 2-[(diphenylmethylidene)amino]-3-[5-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]propanenitrile, 1 mL of HCl (1 M), 30 mL of THF, and 3 mL of H2O were added to a 100 mL round-bottom flask at room temperature. The resulting mixture was stirred at room temperature for a further 3 hours. The resulting mixture was extracted with Et2O (1 × 50 mL). The organic layer was extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded 2-amino-3-[5-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophene-2-yl]propanenitrile (220 mg, 64.6%) as a white solid. LCMS(ES,m / z):[M+H] + :350

[0443] Synthesis of (2S)-N-{1-cyano-2-[5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophen-2-yl]ethyl}-1,4-oxazepan-2-carboxamide [ka] A solution of 2-amino-3-[5-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]propanenitrile (156 mg, 0.44 mmol, 1.1 equivalents) in DCM (5 mL) was treated with (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepan-2-carboxylic acid (100 mg, 0.40 mmol, 1.0 equivalent) and DIEA (158 mg, 1.22 mmol, 3.0 equivalents), followed by the addition of HATU (186 mg, 0.49 mmol, 1.2 equivalents) in several portions at 0°C. The resulting mixture was stirred at 0°C for a further 2 hours. The residue was purified by silica gel column chromatography eluting with PE / THF (1:1) to obtain (2S)-N-{1-cyano-2-[5-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]ethyl}-1,4-oxazepan-2-carboxamide (220 mg, crude product) as a white solid. LCMS(ES,m / z):[M+H] + :577

[0444] Synthesis of (2S)-N-{1-cyano-2-[5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophen-2-yl]ethyl}-1,4-oxazepan-2-carboxamide [ka] To an 8 mL vial, tert-butyl(2S)-2-({1-cyano-2-[5-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate (100 mg, 0.17 mmol, 1.0 equivalent), TsOH (89 mg, 0.51 mmol, 3.0 equivalents), and ACN (3 mL) were added at room temperature. The resulting mixture was stirred at room temperature for a further 3 hours. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH3, H2O) in water, gradient from 10% to 50% over 10 mins; detector, UV 254 nm. This yielded (2S)-N-{1-cyano-2-[5-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]ethyl}-1,4-oxazepan-2-carboxamide (21.9 mg, 26.50%) as a white solid. Analysis data LCMS(ES,m / z):[M+H] + :477.2. 1 H NMR(400MHz,DMSO-d6) δ 8.73(d,J=8.3Hz,1H),8.11(t,J=2.3Hz,1H),8.06-7.98(m,1H),7.71-7.63(m,2H),7.49(d,J=8.4Hz, 1H),7.43(d,J=8.3Hz,1H),7.38(s,1H),5.10(dq,J=15.4,8.2Hz,1H),4.00(ddd,J=25.9,7.9,3.6Hz, 1H),3.94-3.84(m,1H),3.81-3.67(m,1H),3.62-3.46(m,2H),3.43(s,3H),3.15(dd,J=14.2,3.7Hz,1 H),3.06(dd,J=14.2,3.6Hz,1H),2.85-2.67(m,2H),2.60(dd,J=14.4,8.1Hz,1H),1.81-1.67(m,2H).

[0445] Example 12. Synthesis of Compound 115a: (2S)-N-{1-cyano-2-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophen-2-yl]ethyl}-1,4-oxazepan-2-carboxamide [ka] Synthesis of 5-bromo-3-fluoro-1-benzothiophene-2-carboxylic acid [ka] To a stirred solution of 5-bromo-1-benzothiophene-2-carboxylic acid (10 g, 38.90 mmol, 1 equivalent) in THF (300 mL), LDA (2 M in THF) (97 mL, 194 mmol, 5 equivalents) was added dropwise at -78°C under a nitrogen atmosphere. The resulting mixture was stirred at -78°C under a nitrogen atmosphere for 1 hour. To the above mixture, NFSI (61.32 g, 194 mmol, 5 equivalents) in THF (300 mL) was added dropwise at -78°C for 30 minutes. The resulting mixture was stirred at room temperature for a further 16 hours. The reaction products were quenched with water at room temperature. The mixture was acidified to pH 7-8 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with RINKAN (3 × 100 mL). The combined aqueous layer was acidified to pH 4 with concentrated HCl. The precipitated solid was collected by filtration and washed with H2O (3 × 60 mL). This yielded 5-bromo-3-fluoro-1-benzothiophene-2-carboxylic acid (7g, 65.42%) as an off-white solid. LCMS(ES,m / z):[MH] - :273.

[0446] Synthesis of (5-bromo-3-fluoro-1-benzothiophen-2-yl)methanol [ka] 5-bromo-3-fluoro-1-benzothiophen-2-carboxylic acid (1.5 g, 5.45 mmol, 1 equivalent) and THF (30 mL) were stirred together, and BH3-Me2S (1.24 g, 16.36 mmol, 3 equivalents) was added dropwise at 0°C. The resulting mixture was stirred at 60°C for 16 hours. The reaction product was quenched with MeOH at room temperature. The resulting mixture was extracted with RINKAN (3 × 50 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to obtain (5-bromo-3-fluoro-1-benzothiophen-2-yl)methanol (1 g, 70.24%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6) δ 7.96(dd,J=8.6,1.9Hz,1H),7.92(d,J=2.0Hz,1H),7.58(dd,J=8.6,2.0Hz,1H),5.77(t,J=5.8Hz,1H),4.74(dd,J=5.8,1.8Hz,2H).

[0447] Synthesis of 5-bromo-2-(bromomethyl)-3-fluoro-1-benzothiophene [ka] To a stirred solution of (5-bromo-3-fluoro-1-benzothiophen-2-yl)methanol (950 mg, 3.64 mmol, 1 equivalent) and NBS (777 mg, 4.37 mmol, 1.2 equivalents) in DCM (20 mL), PPh3 (1145 mg, 4.37 mmol, 1.2 equivalents) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The resulting mixture was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded 5-bromo-2-(bromomethyl)-3-fluoro-1-benzothiophene (1.1 g, 93.31%) as a pale yellow oil.

[0448] Synthesis of 3-(5-bromo-3-fluoro-1-benzothiophen-2-yl)-2-[(diphenylmethylidene)amino]propanenitrile [ka] A solution of 5-bromo-2-(bromomethyl)-3-fluoro-1-benzothiophene (1.1 g, 3.40 mmol, 1 equivalent) in THF (10 mL) was mixed with 2-[(diphenylmethylidene)amino]acetonitrile (0.75 g, 3.40 mmol, 1 equivalent), benzyltrimethylazanium chloride (0.06 g, 0.34 mmol, 0.1 equivalent), and NaOH (0.27 g, 6.79 mmol, 2 equivalents) in H2O (2 mL) and stirred at 60°C for 4 hours. The resulting mixture was extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (5:1) to obtain 3-(5-bromo-3-fluoro-1-benzothiophen-2-yl)-2-[(diphenylmethylidene)amino]propanenitrile (1.5 g, 95.35%) as an off-white solid. LCMS(ES,m / z):[M+H] + :463.

[0449] Synthesis of 2-[(diphenylmethylidene)amino]-3-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]propanenitrile [ka] A solution of 3-(5-bromo-3-fluoro-1-benzothiophen-2-yl)-2-[(diphenylmethylidene)amino]propanenitrile (800 mg, 1.73 mmol, 1 equivalent), K2CO3 (477 mg, 3.45 mmol, 2 equivalents), 3-methyl-5-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazole-2-one (496 mg, 1.90 mmol, 1.1 equivalents), and Pd(dppf)Cl2 (131 mg, 0.18 mmol, 0.1 equivalents) in 1,4-dioxane (10 mL) was mixed with H2O (1.5 mL) and stirred at 80°C for 2 hours under a nitrogen atmosphere. The residue was purified by silica gel column chromatography eluted with PE / THF (5:1) to obtain 2-[(diphenylmethylidene)amino]-3-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]propanenitrile (700 mg, 76.27%) as a pale yellow oil. LCMS(ES,m / z):[M+H] + :532.

[0450] Synthesis of 2-amino-3-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]propanenitrile [ka] 700 mg (1.32 mmol, 1 equivalent) of 2-[(diphenylmethylidene)amino]-3-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]propanenitrile, along with 30 mL of THF, 3 mL of H2O, and 2 mL of HCl (10.00 mmol, 7.59 equivalents), were added to a 100 mL round-bottom flask at room temperature. The resulting mixture was stirred at room temperature for a further 3 hours. The mixture was basicized to pH 12 with NaOH. The resulting mixture was extracted with ELISA (3 × 50 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / THF (1:2) to obtain 2-amino-3-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophene-2-yl]propanenitrile (350 mg, 72.35%) as a white solid. LCMS(ES,m / z):[M+H] + :368.

[0451] Synthesis of tert-butyl(2S)-2-({1-cyano-2-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]ethyl}carbamoyl)-1,4-oxazepan-4-carboxylate [ka] HATU (112 mg, 0.29 mmol, 1.2 equivalents) was added in several portions at 0°C to a stirred mixture of 2-amino-3-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]propanenitrile (99 mg, 0.270 mmol, 1.1 equivalents), (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepan-2-carboxylic acid (60 mg, 0.25 mmol, 1.00 equivalent), and DIEA (95 mg, 0.74 mmol, 3 equivalents) in DCM (5 mL). The resulting mixture was stirred at 0°C for a further 3 hours. The residue was purified by silica gel column chromatography eluting with PE / THF (1:1) to obtain tert-butyl(2S)-2-({1-cyano-2-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate (120 mg, 82.49%) as a pale yellow oil. LCMS(ES,m / z):[M+H] + :595.

[0452] Synthesis of (2S)-N-{1-cyano-2-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophen-2-yl]ethyl}-1,4-oxazepan-2-carboxamide [ka] In a 50 mL round-bottom flask, tert-butyl(2S)-2-({1-cyano-2-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate (120 mg, 0.20 mmol, 1 equivalent), TsOH (108 mg, 0.62 mmol, 3.0 equivalents), and ACN (3 mL) were added at room temperature. The resulting mixture was stirred at room temperature for a further 3 hours. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH3, H2O) in water, gradient from 10% to 50% over 10 minutes; detector, UV 254 nm. This yielded (2S)-N-{1-cyano-2-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophen-2-yl]ethyl}-1,4-oxazepan-2-carboxamide (20 mg, 20.04%) as a white solid. Analysis data LCMS(ES,m / z):[M+H] + :495. 1 1H NMR (400MHz, DMSO-d6) 1 1H NMR (300MHz, DMSO-d6) δ 8.81(d,J=8.5Hz,1H),8.12-8.01(m,2H),7.81(d,J=8.5Hz,1H),7.74(t,J=1.8 Hz,1H),7.59-7.49(m,1H),7.44(d,J=8.3Hz,1H),5.14-5.03(m,1H),4.07-3.8 2(m,2H),3.74(td,J=7.8,3.5Hz,1H),3.58(dd,J=14.5,7.0Hz,1H),3.51-3.43 (m,1H),3.44(s,3H),3.22-3.02(m,1H),2.88-2.58(m,4H),1.78-1.67(m,2H).

[0453] Example 13. Synthesis of Compound 130a: (2S)-N-{1-cyano-2-[3-fluoro-6-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]ethyl}-1,4-oxazepan-2-carboxamide [ka] Synthesis of 6-bromo-3-fluoro-1-benzothiophene-2-carboxylic acid [ka] To a solution of 6-bromo-1-benzothiophene-2-carboxylic acid (5.5 g, 21.39 mmol, 1.0 equivalent) in THF (100 mL), LDA (2 M in THF) (53.5 mL, 106.96 mmol, 5.0 equivalent) was added dropwise at -78°C under a nitrogen atmosphere. After addition, the mixture was stirred for 1 hour, and then NFSI (33.7 g, 106.96 mmol, 5.0 equivalent) in THF (50 mL) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 12 hours. The reaction mixture was quenched with HCl (aqueous solution) (200 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 6-bromo-3-fluoro-1-benzothiophene-2-carboxylic acid (1.9 g, 32%) as a yellow solid, which was used in the next step without further purification.

[0454] Synthesis of (6-bromo-3-fluoro-1-benzothiophen-2-yl)methanol [ka] To a solution of 6-bromo-3-fluoro-1-benzothiophen-2-carboxylic acid (1.9 g, 6.90 mmol, 1.0 equivalent) in THF (30 mL), B2H6 (1 M in THF) was added at room temperature under a nitrogen atmosphere. The reaction mixture was heated to 60 °C and stirred for 3 hours. The reaction mixture was cooled to room temperature, quenched with HCl (1 N) (20 mL), diluted with water (30 mL), and extracted with ethyl acetate (50 mL x 2). The combined organic phase was dried on anhydrous sodium. After filtration, the filtrate was concentrated and purified by silica gel column chromatography containing 5-10% ethyl acetate / petroleum ether to obtain (6-bromo-3-fluoro-1-benzothiophen-2-yl)methanol (1 g, 55.4%) as a white solid. LCMS (ES, m / z): [M-H2O+H] + :243.

[0455] Synthesis of 6-bromo-2-(bromomethyl)-3-fluoro-1-benzothiophene [ka] A solution of (6-bromo-3-fluoro-1-benzothiophen-2-yl)methanol (1.0 g, 3.83 mmol, 1.0 equivalent) and NBS (0.8 g, 4.59 mmol, 1.2 equivalents) in DCM (10 mL) was stirred at room temperature under a nitrogen atmosphere for 3 hours. The solution was concentrated to remove the solvent, and the residue was purified by silica gel column chromatography eluted with PE / EA (10:1) to obtain 6-bromo-2-(bromomethyl)-3-fluoro-1-benzothiophene (1.0 g, 80.5%) as a white solid (no LCMS signal).

[0456] Synthesis of 3-(6-bromo-3-fluoro-1-benzothiophen-2-yl)-2-[(diphenylmethylidene)amino]propanenitrile [ka] A solution of 6-bromo-2-(bromomethyl)-3-fluoro-1-benzothiophene (1.0 g, 3.08 mmol, 1.0 equivalent) in THF (10 mL) was mixed with 2-[(diphenylmethylidene)amino]acetonitrile (0.7 g, 3.08 mmol, 1.0 equivalent), benzyltrimethylazanium chloride (0.1 g, 0.30 mmol, 0.1 equivalent), and NaOH (0.3 g, 6.17 mmol, 2.0 equivalent) in H2O (2 mL) and stirred at 60°C for 2 hours. The resulting mixture was diluted with water (20 mL) and extracted with SiO (3 × 50 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / THF (5:1) to obtain 3-(6-bromo-3-fluoro-1-benzothiophen-2-yl)-2-[(diphenylmethylidene)amino]propanenitrile (1.3 g, 90.9%) as a yellow solid. LCMS(ES,m / z):[M+H] + :463.

[0457] Synthesis of 2-[(diphenylmethylidene)amino]-3-[3-fluoro-6-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]propanenitrile [ka] To a mixture of 1,4-dioxane (10 mL) and H2O (1 mL) containing 3-(6-bromo-3-fluoro-1-benzothiophen-2-yl)-2-[(diphenylmethylidene)amino]propanenitrile (1.3 g, 2.80 mmol, 1.1 equivalents) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazole-2-one (0.7 g, 2.55 mmol, 1.0 equivalent), K2CO3 (0.7 g, 5.10 mmol, 2.0 equivalents) and Pd(dppf)Cl2 (0.2 g, 0.25 mmol, 0.1 equivalents) were added sequentially. The reaction mixture was stirred under a nitrogen atmosphere at 80°C for 3 hours. The reaction mixture was cooled to room temperature, concentrated, and the solvent removed. The residue was purified by silica gel column chromatography using PE / THF (1:1) elution to obtain 2-[(diphenylmethylidene)amino]-3-[3-fluoro-6-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]propanenitrile (1.3 g, 95.8%) as a yellow oil. LCMS(ES,m / z):[M+H] + :532.

[0458] Synthesis of 2-amino-3-[3-fluoro-6-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]propanenitrile [ka] 2-[(diphenylmethylidene)amino]-3-[3-fluoro-6-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]propanenitrile (1.3 g, 2.44 mmol, 1.0 equivalent), HCl (1 M) (3 mL), and H2O (6 mL) were added to a 100 mL round-bottom flask at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was extracted with Et2O (1 × 50 mL). The mixture was basicized to approximately pH 12 with NaOH (2 M in water). The aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded 2-amino-3-[3-fluoro-6-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophene-2-yl]propanenitrile (560 mg, 62.3%) as a white solid. LCMS(ES,m / z):[M+H] + :367.

[0459] Synthesis of tert-butyl(2S)-2-({1-cyano-2-[3-fluoro-6-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]ethyl}carbamoyl)-1,4-oxazepan-4-carboxylate [ka] A solution of 2-amino-3-[3-fluoro-6-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]propanenitrile (89 mg, 0.24 mmol, 1.2 equivalents) in DMF (2 mL) was treated with (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepan-2-carboxylic acid (50 mg, 0.20 mmol, 1.0 equivalent) and DIEA (79 mg, 0.61 mmol, 3.0 equivalents), followed by the addition of HATU (93 mg, 0.24 mmol, 1.2 equivalents) in several portions at 0°C. The resulting mixture was stirred for a further 2 hours at 0°C. The residue was purified by silica gel column chromatography eluting with PE / THF (1:1) to obtain tert-butyl(2S)-2-({1-cyano-2-[3-fluoro-6-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate (100 mg, 82.4%) as a colorless oil. LCMS(ES,m / z):[M+H] + :595.

[0460] Synthesis of (2S)-N-{1-cyano-2-[3-fluoro-6-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophen-2-yl]ethyl}-1,4-oxazepan-2-carboxamide [ka] In a 25 mL round-bottom flask, tert-butyl(2S)-2-({1-cyano-2-[3-fluoro-6-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate (100 mg, 0.16 mmol, 1.0 equivalent) and TsOH.H2O (96 mg, 0.50 mmol, 3.0 equivalents) were added in ACN (3 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The reaction solution was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel - 120 g; mobile phase, MeCN in water (0.1% NH3.H2O), 10% to 50% gradient over 10 mins; detector, UV 254 nm. This yielded (2S)-N-{1-cyano-2-[3-fluoro-6-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-2-yl]ethyl}-1,4-oxazepan-2-carboxamide (20.5 mg, 24.6%) as a white solid. Analysis data LCMS(ES,m / z):[M+H] + :495.4 1 H NMR(400MHz,DMSO-d6) δ 8.80(dd,J=8.5,1.3Hz,1H),8.34(s,1H),7.83(t,J=1.6Hz,2H),7.72(d,J=1.9Hz,1H),7. 53(dd,J=8.4,1.9Hz,1H),7.44(d,J=8.3Hz,1H),5.08(dtd,J=11.4,8.4,6.9Hz,1H),4.06 -3.84(m,2H),3.74(ddt,J=12.2,8.1,4.3Hz,1H),3.56(ddd,J=14.6,6.9,2.3Hz,1H),3.5 1-3.42(m,4H),3.11(ddd,J=35.1,14.2,3.6Hz,1H),2.87-2.54(m,3H),1.88-1.62(m,2H).

[0461] Example 14. Synthesis of Compound 131a: (2S)-N-{1-cyano-2-[2-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-5-yl]ethyl}-1,4-oxazepan-2-carboxamide [ka] Synthesis of methyl 2-bromobenzo[b]thiophene-5-carboxylate [ka] To a stirred solution of methylbenzo[b]thiophene-5-carboxylate (2 g, 10.40 mmol, 1.0 equivalent) and THF (30 mL), LDA (2 M in THF) (6.24 mL, 12.48 mmol, 1.2 equivalents) was added dropwise at -78°C under a nitrogen atmosphere. The resulting mixture was stirred at -78°C under a nitrogen atmosphere for 1 hour. Dibromoethane (2.15 g, 11.44 mmol, 1.1 equivalents) was added dropwise to the above mixture at -78°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for a further 1 hour. The reaction products were quenched by adding water (50 mL) at room temperature and extracted with SiO2 (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA (12:1) elution to obtain methyl 2-bromobenzo[b]thiophene-5-carboxylate (1.7 g, 60%) as a pale yellow oil. 1 H NMR(400MHz,DMSO-d6) δ 8.44(s,1H),8.10(d,J=8.5Hz,1H),7.91(dd,J=8.5,1.6Hz,1H),7.81(s,1H),3.90(s,3H).

[0462] Synthesis of (2-bromo-1-benzothiophen-5-yl)methanol [ka] To a solution of 2-bromobenzo[b]thiophene-5-carboxylate methyl (1.3 g, 4.79 mmol, 1.0 equivalent) and tetrahydrofuran (25 mL), DIBAL-H (14.4 mL, 14.38 mmol, 3.0 equivalent) (1 M in toluene) was added dropwise at -78°C under a nitrogen atmosphere. After addition, the mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction product was quenched with HCl (1 N) (10 mL) at 0°C, diluted with water (20 mL), and extracted with RINKAN (2 × 50 mL). The combined organic layer was washed with brine (50 mL) and dried on anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to obtain (2-bromo-1-benzothiophene-5-yl)methanol (1.0 g, 85.7%) as a white solid. LCMS(ES,m / z):[M-H2O+H] + :225.

[0463] Synthesis of 2-bromo-5-(bromomethyl)-1-benzothiophene [ka] A solution of (2-bromo-1-benzothiophen-5-yl)methanol (1 g, 4.11 mmol, 1.0 equivalent) in Et2O (10 mL) was treated with PBr3 (0.6 g, 2.05 mmol, 0.5 equivalent) at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction product was quenched with water (20 mL) at 0°C, extracted with ethyl acetate (30 mL), washed with brine (30 mL), and dried on anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to obtain 2-bromo-5-(bromomethyl)-1-benzothiophene (700 mg, 55.6%) as a white solid (no LCMS signal).

[0464] Synthesis of 3-(2-bromo-1-benzothiophen-5-yl)-2-[(diphenylmethylidene)amino]propanenitrile [ka] To a solution of 2-bromo-5-(bromomethyl)-1-benzothiophene (600 mg, 1.96 mmol, 1.0 equivalent) in DCM (5 mL), 2-[(diphenylmethylidene)amino]acetonitrile (432 mg, 1.96 mmol, 1.0 equivalent), benzyltrimethylazanium chloride (36 mg, 0.19 mmol, 0.1 equivalent), NaOH (159 mg, 3.92 mmol, 2.0 equivalent), and H2O (1 mL) were added in order. The mixture was stirred at 40°C for 36 hours. The reaction solution was diluted with water (20 mL) and extracted with CH2Cl2 (2 × 30 mL). The combined organic layers were washed with brine (30 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / THF (5:1) to obtain 3-(2-bromo-1-benzothiophen-5-yl)-2-[(diphenylmethylidene)amino]propanenitrile (800 mg, crude product) as a yellow solid. LCMS(ES,m / z):[M+H] + :445.

[0465] Synthesis of 2-[(diphenylmethylidene)amino]-3-[2-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-5-yl]propanenitrile [ka] To a solution of 3-(2-bromo-1-benzothiophen-5-yl)-2-[(diphenylmethylidene)amino]propanenitrile (350 mg, 0.78 mmol, 1.0 equivalent) and 3-methyl-5-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazole-2-one (205 mg, 0.78 mmol, 1.0 equivalent) in 1,4-dioxane (10 mL) and H2O (1 mL), K2CO3 (217 mg, 1.57 mmol, 2.0 equivalents) and Pd(dppf)Cl2 (58 mg, 0.07 mmol, 0.1 equivalent) were added under a nitrogen atmosphere. The mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature, concentrated, and the solvent was removed. The residue was purified by silica gel column chromatography eluted with PE / THF (5:1) to obtain 2-[(diphenylmethylidene)amino]-3-[2-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophene-5-yl]propanenitrile (120 mg, 30%) as a white solid. LCMS(ES,m / z):[M+H] + :514.

[0466] Synthesis of 2-amino-3-[2-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophene-5-yl]propanenitrile [ka] 350 mg (0.68 mmol, 1.0 equivalent) of 2-[(diphenylmethylidene)amino]-3-[2-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-5-yl]propanenitrile, 30 mL of THF, and 3 mL of H2O were added to a 100 mL round-bottom flask at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The mixture was basicized to pH 12 with NaOH (2N). The resulting mixture was extracted with ELISA (2 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / THF (1:2) to obtain 2-amino-3-[2-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophene-5-yl]propanenitrile (120 mg, 50.4%) as a white solid. LCMS(ES,m / z):[M+H] + :349.

[0467] Synthesis of tert-butyl(2S)-2-({1-cyano-2-[2-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophen-5-yl]ethyl}carbamoyl)-1,4-oxazepan-4-carboxylate [ka] HATU (119 mg, 0.31 mmol, 1.2 equivalents) was added in several portions at 0°C to a stirred mixture of 2-amino-3-[2-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophene-5-yl]propanenitrile (110 mg, 0.31 mmol, 1.2 equivalents), (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepan-2-carboxylic acid (64 mg, 0.26 mmol, 1.0 equivalent), and DIEA (102 mg, 0.78 mmol, 3.0 equivalents) in DCM (5 mL). The resulting mixture was stirred further at 0°C for 3 hours. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with PE / THF (1:1) to obtain tert-butyl(2S)-2-({1-cyano-2-[2-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophene-5-yl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate (120 mg, 79%) as a white solid. LCMS(ES,m / z):[M+H] + :577.

[0468] Synthesis of (2S)-N-{1-cyano-2-[2-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)-1-benzothiophene-5-yl]ethyl}-1,4-oxazepan-2-carboxamide [ka] In a 25 mL round-bottom flask, tert-butyl(2S)-2-{[(1S)-1-cyano-2-[2-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-5-yl]ethyl}carbamoyl}-1,4-oxazepane-4-carboxylate (120 mg, 0.20 mmol, 1.0 equivalent), TsOH (108 mg, 0.62 mmol, 3.0 equivalents), and ACN (3 mL) were added at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The reaction solution was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel - 120 g; mobile phase, MeCN in water (0.1% NH3, H2O), 10% to 50% gradient over 10 mins; detector, UV 254 nm. This yielded (2S)-N-{1-cyano-2-[2-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)-1-benzothiophen-5-yl]ethyl}-1,4-oxazepan-2-carboxamide (16.3 mg, 16.44%) as a white solid. Analysis data LCMS(ES,m / z):[M+H] + :477.2 1 H NMR(400MHz,DMSO-d6) δ 8.61(dd,J=8.4,6.0Hz,1H),7.93(dd,J=8.2,3.0Hz,1H),7.86(d,J=2.2Hz,1H),7. 75-7.73(m,2H),7.51(d,J=8.4Hz,1H),7.43(d,J=8.3Hz,1H),7.30(d,J=8.3Hz,1H) ,5.10-4.97(m,1H),4.00-3.80(m,2H),3.75-3.67(m,1H),3.43(s,3H),3.29-3.26( m,2H),3.14-2.97(m,1H),2.83-2.63(m,2H),2.56-2.41(m,2H),1.78-1.68(m,2H).

[0469] Example 15. Synthesis of (2S)-N-(1-cyano-2-(3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)bicyclo[1.1.1]pentan-1-yl)ethyl)-1,4-oxazepan-2-carboxamide (compound 101e) Methyl 3-phenylbicyclo[1.1.1]pentane-1-carboxylate, [ka] 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (2.00 g, 1 equivalent, 11.8 mmol) and lead tetraacetate (6.86 g, 95% by weight, 1.25 equivalents, 14.7 mmol) were dissolved in benzene (214 mL), and the flask was placed in a condenser closed with a septum and a small N2 balloon (CO2 release). The mixture was irradiated with a 400 W tungsten lamp for 6 hours, forming a large amount of white inorganic precipitate. After cooling the reaction flask, the white suspension was filtered through a short Celite pad (30 g), and the Celite pad was washed with a 1:4 ethyl acetate:cyclohexane mixture (3 × 100 mL). The clear, colorless filtrate was then concentrated under reduced pressure to obtain 2.82 g of crude product. Purification by flash column chromatography: 80 g [cHex / EA] - 0% - 1 CV, then 0-15% - 2 CV, and 15% - 4 CV. Methyl 3-phenylbicyclo[1.1.1]pentane-1-carboxylate (1.68 g, 8.31 mmol - yield 71%) was obtained as a colorless oil. TLC:cHex / DCM / EA 90:5:5, The product can be visualized by KMnO4 staining. 1H NMR(400MHz,DMSO) δ 7.35-7.29(m,2H),7.28-7.21(m,3H),3.64(s,3H),2.26(s,6H).

[0470] 3-Phenylbicyclo[1.1.1]pentane-1-carboxylic acid [ka] Lithium hydroxide monohydrate (663.9 mg, 2 equivalents, 15.82 mmol) was added in a single step to a biphasic solution of methyl 3-phenylbicyclo[1.1.1]pentane-1-carboxylate (1600 mg, 1 equivalent, 7.911 mmol) in a mixture of THF (79.0 mL) and H2O (79.0 mL). The reaction mixture was stirred at 25°C for 16 hours. The conversion was determined by LC-MS-complete conversion. The basic mixture was diluted with 200 mL of water and washed with 2 × 50 mL of DCM. LC-MS of the organic phase revealed no product, only impurities. The aqueous phase was acidified with 1 M KHSO4 (20 mL) and extracted with ELISA (3 × 100 mL). The combined organic matter was dried over anhydrous Na2SO4, filtered, concentrated, and dried to obtain 3-phenylbicyclo[1.1.1]pentane-1-carboxylic acid (1.31 g, 6.96 mmol - yield 88%) as a white solid. or, To a biphasic solution of crude methyl 3-phenylbicyclo[1.1.1]pentane-1-carboxylate (estimated at 4750 mg, 1 equivalent, 23.50 mmol) in a mixture of THF (235 mL) and H2O (235 mL), excess sodium hydroxide (2.82 g, 3 equivalents, 70.50 mmol) was added in one step. The reaction mixture was stirred at 25°C for 16 hours. The conversion was determined by LC-MS-complete conversion. Purification as described above yields 3-phenylbicyclo[1.1.1]pentane-1-carboxylic acid in slightly better overall yield (2.96 g, 15.70 mmol - 67% yield in two steps). The product can be visualized by KMnO4 staining. 1H NMR(400MHz,DMSO) δ 12.40(s,1H),7.35-7.29(m,2H),7.27-7.20(m,3H),2.21(s,6H).

[0471] 3-Phenylbicyclo[1.1.1]pentane-1-carboxamide [ka] To a solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (1430 mg, 1 equivalent, 7.597 mmol) and oxalyl chloride (1253 mg, 1.3 equivalents, 9.876 mmol, 864.5 μL) in Et2O (38 mL), DMF (55 mg, 0.1 equivalents, 0.76 mmol, 60 μL) was added dropwise as a catalyst. The mixture was stirred for approximately 2 hours until no further gas release was observed. TLC-[EA]--->[20 μL sample was taken and quenched with MeOH], visualization by KMnO4 staining shows complete consumption of SM - less polar spot formation. The reaction mixture was concentrated and dried in a rotary evaporator to obtain an orange liquid, which was used as the crude product in the next step. The crude product 3-phenylbicyclo[1.1.1]pentane-1-carbonyl chloride (estimated at 1.570 g, 1 equivalent, 7.597 mmol) was dissolved in DCM (44 mL) and added dropwise over 15 minutes to a cold (-20°C) ammonia solution in MeOH (5.175 g, 43.5 mL, 7 mol, 40 equivalents, 304 mmol). The mixture was stirred at -20°C for a further 2 hours and then left overnight (16 hours) to reach 25°C. LCMS demonstrates the complete transformation of the starting materials. The reaction mixture was concentrated under vacuum and evaporated twice with CH2Cl2. The solid was dissolved in DCM (150 mL), washed with NaHCO3 / brine[2:8] (150 mL) and brine (150 mL), dried, and evaporated to obtain 3-phenylbicyclo[1.1.1]pentane-1-carboxamide (1.35 g, 7.21 mmol - yield 95%) as a white solid. 1H NMR(400MHz,DMSO) δ 7.36-7.27(m,3H),7.27-7.18(m,3H),6.96(s,1H),2.14(s,6H). or, The crude product 3-phenylbicyclo[1.1.1]pentane-1-carbonyl chloride (estimated at 1.437 g, 1 equivalent, 6.954 mmol) was dissolved in DCM (70 mL), cooled to 0°C, and ammonium chloride (1.488 g, 4 equivalents, 27.82 mmol) was added all at once, followed by the dropwise addition of triethylamine (7.037 g, 9.69 mL, 10 equivalents, 69.54 mmol). The mixture was stirred at 0°C for 2 hours, then allowed to reach 25°C overnight, and stirring was continued over the weekend. LC-MS showed a mixture of acid and amide. The compounds were separated by extraction in 2 M HCl / 1 M NaOH.

[0472] 3-Phenylbicyclo[1.1.1]pentane-1-carbonitride [ka] To an ice-cold solution of 3-phenylbicyclo[1.1.1]pentane-1-carboxamide (1.311 g, 1 equivalent, 7.000 mmol) in dry DCM (70.00 mL), triethylamine (3.542 g, 4.88 mL, 5 equivalents, 35.00 mmol) was added, followed by dropwise addition of trifluoroacetic anhydride (2.940 g, 1.955 mL, 2 equivalents, 14.00 mmol). The resulting reaction mixture was brought to 25°C and stirred for 18 hours. After LCMS showed complete conversion of the starting materials, the mixture was cooled by an ice bath in a flask, the reaction product was quenched with NaHCO3 (30 mL), extracted with DCM (2 × 50 mL), and then the organic layer was washed with water and brine to pH 2 with 1N KHSO4, and the organic extract was dried over anhydrous Na2SO4. Purification by flash column chromatography: 20 g [pentane / Et2O] - 0% - 1 CV, then 0-15% - 1 CV, and 15% - 4 CV. 3-phenylbicyclo[1.1.1]pentane-1-carbonitrile (1.185 g, 7.00 mmol - yield over 99%) was obtained as a colorless oil. 1H NMR (400MHz, CDCl3) δ 7.35-7.27(m,3H),7.19-7.15(m,2H),2.51(s,6H).

[0473] 5-(4-(3-cyanobicyclo[1.1.1]pentan-1-yl)phenyl)-5H-thianthrene-5-iumtetrafluoroborate, [ka] Under ambient atmosphere, 50 mL of RBF was sequentially packed with 3-phenylbicyclo[1.1.1]pentane-1-carbonitride (694 mg, 4.10 mmol), thiantrene-S-oxide (1.0 g, 1.05 equivalents, 4.30 mmol), and dry MeCN (20.5 ml, c=0.20 M). After most of the solid had dissolved (approximately 5 minutes), the solution was cooled to -35°C, and then TFAA (2.58 g, 1.74 mL, 3.0 equivalents, 12.30 mmol) was added all at once, followed by tetrafluoroboric acid (1.32 g, 1.11 mL, 2.0 equivalents, 8.20 mmol) dropwise. The mixture was warmed to 23°C over 1.5 hours and stirred at room temperature for another 1.5 hours. Complete conversion of LCMS-SM is shown. The solution was then diluted with 150 ml of DCM and poured into a separatory funnel. The organic layer was washed with 50 mL of NaHCO3 / 100 mL of brine, and the aqueous phase was extracted three times with 50 mL of DCM. The combined organic extracts were washed with 150 mL of 10% NaBF4 aqueous solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography using FCC-12g silica, [DCM / MeOH---2CV-100%-DCM, followed by 4CV 0-10%, and then 4CV-10% (pure product in 8-10% methanol). The product (1.35g, 2.86 mmol, 70%) was obtained. TLC (DCM:MeOH 9:1), product rf 0.42. 1H NMR(400MHz,DMSO) δ 8.56(d,J=6.8Hz,2H),8.05(dd,J=7.8,1.2Hz,2H),7.92(td,J=7.7,1.5Hz,2H),7.8 5(td,J=7.7,1.4Hz,2H),7.38(d,J=8.7Hz,2H),7.16(d,J=8.6Hz,2H),2.50(s,6H).

[0474] 5-(4-(3-(methoxycarbonyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-5H-thianthrene-5-iumtetrafluoroborate [ka] Under ambient atmosphere, 50 mL of RBF was sequentially packed with 3-phenylbicyclo[1.1.1]pentane-1-carbonitrile (1.75 g, 8.65 mmol), thiantrene-S-oxide (2.21 g, 1.10 equivalents, 9.52 mmol), and dry MeCN (43.2 ml, c=0.20 M). After most of the solid had dissolved (approximately 5 minutes), the solution was cooled to -35°C, and then TFAA (5.45 g, 3.66 mL, 3.0 equivalents, 25.96 mmol) was added all at once, followed by tetrafluoroboric acid (2.78 g, 2.35 mL, 2.0 equivalents, 17.31 mmol) dropwise. The mixture was warmed to 23°C over 1.5 hours and stirred at room temperature for another 1.5 hours. Complete conversion of LCMS-SM is shown. Next, the solution was diluted with 150 ml of DCM and poured into a separatory funnel. The organic layer was washed with 50 ml of NaHCO3 / 100 ml of brine, and the aqueous phase was extracted three times with 50 ml of DCM. The combined organic extract was washed with 150 ml of 10% NaBF4 aqueous solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography using FCC-12g silica, [DCM / MeOH---2CV-100%-DCM, followed by 4CV 0-10%, and then 4CV-10% (pure product in 8-10% methanol). The product (3.06g, 6.08 mmol, 70%) was obtained. TLC (DCM:MeOH 9:1), product rf 0.42. 1H NMR(400MHz,DMSO) δ 8.56(dd,J=7.9,1.3Hz,2H),8.06(dd,J=7.9,1.2Hz,2H),7.92(td,J=7.8,1.5Hz,2H),7.85(t d,J=7.7,1.4Hz,2H),7.41(d,J=8.7Hz,2H),7.16(d,J=8.6Hz,2H),3.61(s,3H),2.24(s,6H).

[0475] Methyl 3-(4-hydroxyphenyl)bicyclo[1.1.1]pentane-1-carboxylate [ka] A vial was filled with 5-(4-(3-(methoxycarbonyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-5H-thianthrene-5-ium tetrafluoroborate (252 mg, 1 equivalent, 0.500 mmol), thiophene-2-carboxylate copper(I) (143 mg, 1.5 equivalents, 750 μmol), and (4,4'-di-t-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-(5-trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridium(III) hexafluorophosphate (5.61 mg, 0.01 equivalents, 5.00 μmol). The vial was vacuumed and backfilled three times with nitrogen. MeCN (2.50 mL) and H2O (180 mg, 180 μL, 20 equivalents, 10.0 mmol) were added. A blue LED lamp (450 nm) was installed. The reaction mixture was stirred overnight under irradiation. The lamp was turned off, ethyl acetate was added, and the mixture was filtered over SiO2 and dried in the vial. The crude product was purified to ethyl acetate using MPLC Biotage cyclohexane to obtain methyl 3-(4-hydroxyphenyl)bicyclo[1.1.1]pentane-1-carboxylate (76.0 mg, 70%). 1 H NMR(400MHz,CDCl3) δ 7.12-7.06(m,2H),6.80-6.75(m,2H),3.71(s,3H),2.28(s,6H).

[0476] Ethyl / methyl 3-(4-hydroxy-3-nitrophenyl)bicyclo[1.1.1]pentane-1-carboxylate [ka] To a solution of methyl 3-(4-hydroxyphenyl)bicyclo[1.1.1]pentane-1-carboxylate (305.6 mg, 1 equivalent, 1.400 mmol) in EtOH (14.00 mL), iron(III) nitrate notahydrate (622.2 mg, 1.1 equivalent, 1.540 mmol) was added in one step. The mixture was stirred at 60°C for 3 hours. A 6N HCl aqueous solution was added to the brown solution, and the mixture was extracted by DCM. The organic phases were combined, washed with brine, dried on MgSO4, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using hexane / SiO as the eluent to obtain methyl 3-(4-hydroxy-3-nitrophenyl)bicyclo[1.1.1]pentane-1-carboxylate (158 mg, 600 μmol, 42.9%). A mixture of Me and Et esters. 1 H NMR(400MHz,CDCl3) δ 10.52(s,1H),7.89(d,J=2.2Hz,1H),7.44(dd,J=8.6,2.2Hz,1H),7.11(d,J=8.6 Hz,1H),4.17(q,J=7.1Hz,1H),3.72(s,1H),2.33(2s,6H),1.29(t,J=7.1Hz,2H).

[0477] Ethyl / methyl 3-(3-amino-4-hydroxyphenyl)bicyclo[1.1.1]pentane-1-carboxylate [ka] A flask was packed with 3-(4-hydroxy-3-nitrophenyl)bicyclo[1.1.1]pentane-1-carboxylate (158 mg, 1 equivalent, 600 μmol), palladium on carbon (36.8 mg, 0.576 equivalents, 346 μmol), and MeOH (3.00 mL). The flask was evacuated and refilled three times with N2, then three times with H2. The reaction mixture was filtered after 3 hours. The solvent was removed under vacuum. Crude NMR: Pure. Estimated (quantitative) 1H NMR(60MHz,CDCl3) δ 6.59(s,3H),4.17(m,2H),3.71(s,1H),2.23(s,6H),1.28(t,J=7.2Hz,2H).

[0478] Ethyl / methyl 3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylate [ka] A 4 mL sealed tube was packed with ethyl / methyl 3-(3-amino-4-hydroxyphenyl)bicyclo[1.1.1]pentane-1-carboxylate (140.0 mg, 1 equivalent, 600.2 μmol) + di(1H-imidazole-1-yl)methanone (126.5 mg, 1.3 equivalents, 780.2 μmol) and THF (1.200 mL). The reaction mixture was stirred at 65°C for 16 hours. It was then cooled to room temperature, water was added, and the mixture was extracted with ethyl / methyl

[0479] Ethyl / methyl 3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)bicyclo[1.1.1]pentan-1-carboxylate [ka] In 50 mL of RBF, potassium carbonate (207.37 mg, 2.5 equivalents, 1.50050 mmol) and methyl iodide (170.38 mg, 75.06 μL, 2 equivalents, 1.20040 mmol) were added at room temperature to a solution of ethyl / methyl 3-(2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)bicyclo[1.1.1]pentane-1-carboxylate (155.61 mg, 1 equivalent, 600.200 μmol) in DMF (2.00067 mL). The reaction mixture was stirred at room temperature for 16 hours. Water and precipitate were filtered. The cake was dissolved in siRNA, dried over anhydrous Na2SO4, concentrated, and dried. The residue was purified by FC (SiO2, cyclohexane to cyclohexane: HCl) to obtain ethyl / methyl 3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)bicyclo[1.1.1]pentane-1-carboxylate (145.7 mg, 533.1 μmol, 88.83%) as a solid. This is a mixture of Me and Et esters. 1 H NMR(60MHz,CDCl3) δ 7.22-6.75(m,3H),4.12(m,2H),3.72(s,1H),3.40(s,3H),1.23(m,3H).

[0480] 3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)bicyclo[1.1.1]pentan-1-carboxylic acid [ka] To a solution of 3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)bicyclo[1.1.1]pentane-1-carboxylate (146 mg, 1 equivalent, 534 μmol) in 1,4-dioxane (3.56 mL), HCl 6N (1.78 mL) was added at room temperature. The mixture was stirred at 110 °C for 2 hours. Water was added, and the precipitate was filtered. The cake was dissolved in ethyl acetate, dried over anhydrous sodium 2SO4, concentrated, and dried. Estimated (quantitative) 1H NMR(60MHz,CDCl3) δ 8.77(s,1H),7.21-6.75(m,3H),3.40(s,3H),2.37(s,6H).

[0481] Methyl 2-(bis(tert-butoxycarbonyl)amino)-3-(3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)bicyclo[1.1.1]pentan-1-yl)propanoate [ka] The vial was filled with 3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (50,000 mg, 1 equivalent, 192.86 μmol), 4CzIPN (2.8576 mg, 0.02 equivalents, 3.8571 μmol), 2-(bis(tert-butoxycarbonyl)amino)acrylate (69.738 mg, 1.2 equivalents, 231.43 μmol), dibasic potassium phosphate (83.975 mg, 2.5 equivalents, 482.14 μmol), and DMF (1.9286 mL). The mixture was degassed for 15 minutes. A blue LEDS lamp (Lamp 450) was attached, and the reaction mixture was irradiated for 16 hours. Water was added, and the mixture was extracted with ELISA and Na. 2S The solution was dried on O4, concentrated, and dried again. It was purified with MPLC (cyclohexane / ethylethanol) to obtain methyl 2-(bis(tert-butoxycarbonyl)amino)-3-(3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)bicyclo[1.1.1]pentan-1-yl)propanoate (47.2 mg, 91.4 μmol, 47.4%). 1 H NMR(400MHz,CDCl3) δ 7.13-7.03(m,2H),6.88(d,J=1.9Hz,1H),4.98(dd,J=7.6,3.5Hz,1H),3.71( s, 3H), 3.39 (s, 3H), 2.25-2.19 (m, 1H), 1.82 (t, J=7.8Hz, 6H), 1.51 (s, 18H).

[0482] 2-amino-3-(3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)bicyclo[1.1.1]pentan-1-yl)propanoate [ka] To a solution of methyl 2-(bis(tert-butoxycarbonyl)amino)-3-(3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)bicyclo[1.1.1]pentan-1-yl)propanoate (47.2000 mg, 1 equivalent, 91.368 μmol) in 1,4-dioxane (609.12 μL), HCl 6N (304.56 μL) was added at room temperature. The reaction mixture was stirred at 110°C for 2 hours. The solvent was removed under vacuum. Estimated (quantitative) 1 H NMR(400MHz,D2O) δ 6.89(d,J=8.2Hz,1H),6.84(d,J=8.4Hz,1H),6.78(s,1H),4.12(t,J=5.8H z,1H),3.66(t,J=4.3Hz,1H),3.12(s,3H),2.34-2.21(m,2H),2.02(s,6H).

[0483] 2-((tert-butoxycarbonyl)amino)-3-(3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)bicyclo[1.1.1]pentan-1-yl)propanoic acid [ka] A vial was filled with 2-amino-3-(3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)bicyclo[1.1.1]pentan-1-yl)propanoate (30.955 mg, 1 equivalent, 91.368 μmol), sodium carbonate (96.841 mg, 10 equivalents, 913.68 μmol), and di-tert-butyl dicarbonate (39.882 mg, 40.8 μL, 2.0 equivalents, 182.74 μmol) in a mixture of THF (913.68 μL) and H2O (913.68 μL). The reaction mixture was stirred overnight at room temperature. Saturated NaHCO3 was added, extracted with ethyl acetate, dried over Na2SO4, concentrated and dried to obtain 2-((tert-butoxycarbonyl)amino)-3-(3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)bicyclo[1.1.1]pentan-1-yl)propanoic acid (36.8 mg, 91.4 μmol, 100%), and the quantitative yield was estimated. 1 H NMR(400MHz,CDCl3) δ 7.07(d,J=8.2Hz,1H),6.90(dd,J=8.2,1.7Hz,1H),6.75(d,J=1.6Hz,1H),5.08( d,J=8.5Hz,1H),4.41-4.32(m,1H),3.37(s,3H),2.04-1.88(m,8H),1.45(s,9H).

[0484] tert-butyl(1-amino-3-(3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)bicyclo[1.1.1]pentan-1-yl)-1-oxopropan-2-yl)carbamate [ka] To a solution of 2-((tert-butoxycarbonyl)amino)-3-(3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)bicyclo[1.1.1]pentan-1-yl)propanoic acid (36.771 mg, 1 equivalent, 91.368 μmol) in dry THF (1.8274 mL), triethylamine (27.737 mg, 38.2 μL, 3.000 equivalents, 274.10 μmol) and ethyl chloroformate (14.873 mg, 13.08 μL, 1.5 equivalents, 137.05 μmol) were added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction product is presumed to be quantitative. Ammonia hydrochloride (7.331 mg, 137.05 μL, 1 mole, 1.5 equivalents, 137.05 μmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 hours. 1N KHSO4 was added, the mixture was extracted three times with toluene, dried over Na2SO4, filtered, concentrated, and dried. Estimated (quantitative)

[0485] tert-butyl(1-cyano-2-(3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)bicyclo[1.1.1]pentan-1-yl)ethyl)carbamate [ka] Trifluoroacetic anhydride (28.785 mg, 19.14 μL, 1.5 equivalents, 137.05 μmol) and pyridine (21.68 mg, 22.2 μL, 3 equivalents, 274.10 μmol) were added at 0°C to an ice-cold solution of tert-butyl (1-amino-3-(3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)bicyclo[1.1.1]pentan-1-yl)-1-oxopropan-2-yl) carbamate (36.681 mg, 1 equivalent, 91.368 μmol) in dry THF (913.68 μL). The resulting reaction mixture was stirred for 2 hours. The solvent was removed under vacuum, and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N KHSO4, water, and brine, dried over anhydrous Na2SO4, filtered, concentrated, and dried. Estimated (quantitative) 1H NMR(400MHz,CDCl3) δ 7.12(d,J=8.2Hz,1H),6.96-6.92(m,1H),6.79(d,J=1.6Hz,1H),5.00(s,1H),4.62(s,1H),3.40(s,3H),2.14-2.03(m,8H).

[0486] 2-amino-3-(3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)bicyclo[1.1.1]pentan-1-yl)propanenitrile [ka] In a 10 mL vial, tert-butyl(1-cyano-2-(3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)bicyclo[1.1.1]pentan-1-yl)ethyl)carbamate (35.035 mg, 1 equivalent, 91.368 μmol), MeCN (1 mL), and PTSOH (52.137 mg, 3 equivalents, 274.10 μmol) were added at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled in an ice bath, basicized to 8 with saturated NaHCO3 (aqueous solution), and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (100 mL) and dried on anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. NMR: ok - presumed to be quantitative. 1 H NMR(400MHz,CDCl3) δ 7.10(d,J=8.2Hz,1H),6.93(dd,J=8.2,1.6Hz,1H),6.77(d,J=1.7Hz,1H),3.73 (dd,J=8.1,6.0Hz,1H),3.39(s,3H),2.09(s,6H),2.05(dd,J=8.8,7.0Hz,2H).

[0487] tert-butyl(2S)-2-((1-cyano-2-(3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)bicyclo[1.1.1]pentan-1-yl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate [ka] To a solution of 2-amino-3-(3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)bicyclo[1.1.1]pentan-1-yl)propanenitrile (25.887 mg, 1 equivalent, 91.368 μmol) and (S)-4-(tert-butoxycarbonyl)-1,4-oxazepan-2-carboxylic acid (24.651 mg, 1.1 equivalents, 100.50 μmol) in dry DMF (1 mL), HATU (41.690 mg, 1.2 equivalents, 109.64 μmol) and diisopropylethylamine (17.714 mg, 23.7 μL, 1.5 equivalents, 137.05 μmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to obtain a residue, which was then mixed with a saturated aqueous solution of NaHCO3 (30 mL) at 0°C and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The product obtained was FC DCM / MeOH (0-10%) (32.2 mg, 69%). 1 H NMR(400MHz,CDCl3) δ 7.10(d,J=8.2Hz,1H),6.92(dt,J=8.0,1.4Hz,1H),6.76(q,J=1.8Hz,1H),4.92(s,1H),4. 26-3.98(m,3H),3.65(s,1H),3.59-3.50(m,1H),3.39(s,3H),2.08(s,6H),1.46(2s,9H).

[0488] (2S)-N-(1-cyano-2-(3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)bicyclo[1.1.1]pentan-1-yl)ethyl)-1,4-oxazepan-2-carboxamide [ka] A vial was filled with tert-butyl(2S)-2-((1-cyano-2-(3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)bicyclo[1.1.1]pentan-1-yl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate (32.2 mg, 1 equivalent, 63.1 μmol) and PTSOH (36.0 mg, 3 equivalents, 189 μmol). MeCN (1 mL) was added. The mixture was stirred at room temperature for 3 hours. Saturated NaHCO3 was added, and the mixture was extracted three times with ELISA. The organic layer was dried over Na2SO4, concentrated, and dried. Purification by MPLC (DCM / MeOH) yielded (2S)-N-(1-cyano-2-(3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)bicyclo[1.1.1]pentan-1-yl)ethyl)-1,4-oxazepan-2-carboxamide (13.3 mg, 32.4 μmol, 51.4%). 1 H NMR(400MHz,DMSO) δ 8.64(t,J=8.1Hz,1H),7.22(d,J=8.1Hz,1H),7.08(dd,J=3.2,1.6Hz,1H),6 .91(dt,J=8.1,1.9Hz,1H),4.79-4.70(m,1H),4.08(ddd,J=17.1,8.4,3.5Hz ,1H),3.93(ddt,J=12.3,6.2,4.4Hz,1H),3.75(dtd,J=12.3,7.9,4.2Hz,1H ),3.29(s,2H),2.94-2.73(m,3H),2.16-2.10(m,2H),1.96(d,J=4.2Hz,6H).

[0489] Example 16. Synthesis of (2S)-N-(1-cyano-2-(6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-1H-indole-2-yl)ethyl)-1,4-oxazepan-2-carboxamide (compound 128b) [ka] Synthesis of 1-(tert-butyl)2-ethyl6-bromo-1H-indole-1,2-dicarboxylate [ka] A solution of ethyl 6-bromo-1H-indole-2-carboxylate (2 g, 7.46 mmol, 1.0 equivalent) in DCM (20 mL) was treated at room temperature with TEA (1.51 g, 14.92 mmol, 2.0 equivalents) and DMAP (0.09 g, 0.75 mmol, 0.1 equivalents), and then Boc2O (2.44 g, 11.19 mmol, 1.5 equivalents) was added in several portions at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with DCM (30 mL). The resulting mixture was washed with water (3 × 30 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product 1-tert-butyl 2-ethyl 6-bromoindole-1,2-dicarboxylate (2.6 g, 94.65%) was used directly in the next step as a yellow oil without further purification. LCMS(ES,m / z):[M+H] + :368.

[0490] Synthesis of tert-butyl 6-bromo-2-(hydroxymethyl)-1H-indole-1-carboxylate [ka] A solution of 1-tert-butyl 2-ethyl 6-bromoindole-1,2-dicarboxylate (2.3 g, 6.25 mmol, 1.0 equivalent) in DCM (35 mL) was treated with DIBAL-H (10.41 mL, 15.62 mmol, 2.5 equivalents) and added dropwise at -78°C. The resulting mixture was stirred at -40°C for 2 hours. The reaction was quenched by adding water (20 mL) at 0°C. The resulting mixture was filtered, and the filter cake was washed with Depositphotos (2 × 50 mL). The filtrate was washed with 2 × 50 mL of water. The organic layer was dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product tert-butyl 6-bromo-2-(hydroxymethyl)indole-1-carboxylate (1.8 g, 88.35%) was used directly in the next step as a yellow oil without further purification. LCMS(ES, m / z):[M+H] + :326.

[0491] Synthesis of tert-butyl 6-bromo-2-(chloromethyl)-1H-indole-1-carboxylate [ka] A solution of tert-butyl 6-bromo-2-(hydroxymethyl)indole-1-carboxylate (1.8 g, 5.52 mmol, 1.0 equivalent) in DCM (60 mL) was treated at room temperature with TEA (0.95 g, 9.38 mmol, 1.7 equivalents) and LiCl (2.34 g, 55.18 mmol, 10.0 equivalents), and then MsCl (1.07 g, 9.38 mmol, 1.7 equivalents) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was washed with 2 × 30 mL of water. The organic layer was dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product tert-butyl 6-bromo-2-(chloromethyl)indole-1-carboxylate (1.8 g, 94.65%) was used directly in the next step as a brown oil without further purification. LCMS(ES, m / z):[M+H] + :344.

[0492] Synthesis of tert-butyl 6-bromo-2-(2-cyano-2-((diphenylmethylene)amino)ethyl)-1H-indole-1-carboxylate [ka] A mixture of tert-butyl 6-bromo-2-(chloromethyl)indole-1-carboxylate (1.8 g, 5.22 mmol, 1.0 equivalent), NaOH (0.42 g, 10.45 mmol, 2.0 equivalent), 2-[(diphenylmethylidene)amino]acetonitrile (1.15 g, 5.22 mmol, 1.0 equivalent), and benzyl(chloro)trimethylamine (0.10 g, 0.52 mmol, 0.1 equivalent) in DCM (20 mL) and H2O (2 mL) was stirred at 40°C for 8 hours. The mixture was cooled to room temperature. The resulting mixture was diluted with DCM (30 mL). The resulting mixture was washed with water (2 × 30 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA (10:1) elution to obtain tert-butyl 6-bromo-2-{2-cyano-2-[(diphenylmethylidene)amino]ethyl}-octahydroindole-1-carboxylate (1.2 g, 42.82%) as a brown oil. LCMS(ES,m / z):[M+H] + :528.

[0493] Synthesis of tert-butyl 2-(2-cyano-2-((diphenylmethylene)amino)ethyl)-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-1H-indole-1-carboxylate [ka] A mixture of tert-butyl 6-bromo-2-{2-cyano-2-[(diphenylmethylidene)amino]ethyl}indole-1-carboxylate (1.2 g, 2.27 mmol, 1.0 equivalent), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazole-2-one (0.62 g, 2.27 mmol, 1.0 equivalent), Na2CO3 (0.48 g, 4.54 mmol, 2.0 equivalent), and Pd(dppf)Cl2 (0.17 g, 0.23 mmol, 0.1 equivalent) in dioxane (12 mL) and H2O (1.2 mL) was stirred at 80°C for 16 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with toluene (3 × 50 mL). The combined organic layers were washed with water (2 × 50 mL) and dried on anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (5:1) to obtain tert-butyl 2-{2-cyano-2-[(diphenylmethylidene)amino]ethyl}-6-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)indole-1-carboxylate (1.2 g, 88.56%) as a brown solid. LCMS(ES, m / z):[M+H] + :597.

[0494] Synthesis of tert-butyl 2-(2-amino-2-cyanoethyl)-6-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-1H-indole-1-carboxylate [ka] A solution of tert-butyl 2-{2-cyano-2-[(diphenylmethylidene)amino]ethyl}-6-(3-methyl-2-oxo-1,3-benzoxazole-5-yl)indole-1-carboxylate (1.2 g, 2.01 mmol, 1.0 equivalent) in THF (60 mL) was treated with HCl (1 M) (3 mL) and added dropwise at room temperature. The resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was diluted with water (50 mL). The resulting mixture was washed with 2 × 50 mL of diethyl ether. The residue was basicized to pH 10 with saturated NaHCO3 (aqueous solution). The resulting mixture was e...

Claims

1. Compound of formula (I), 【Chemical Formula 614】 or a pharmaceutically acceptable salt or deuterated form thereof, During the ceremony, R ０ but, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocycle contains 1-3 R ８ A 5-12 member monocyclic heterocycline, which is optionally substituted, or ● A 5-12 membered polycyclic heterocyclil containing 1-3 heteroatoms selected from N, S, or O, wherein the polycyclic heterocycle has 1-3 R ８ These are 5- to 12-membered polycyclic heterocyclines that are optionally substituted, Each R ８ is independently H, halogen, oxo, cyano, hydroxyl, NH ２ , NH(C １－６ alkyl), N(C １－６ alkyl) ２ , COOH, C １－６ alkyl, C １－６ alkyl-OH, -CONH ２ , -S(=O)NH ２ , -S(O) ２ NH ２ , C １－６ alkoxy, halogenated C １－６ alkoxy, C １－６ alkylene-carbocyclic, or C １－６ alkylene-heteroaryl, and is selected from L is a polycyclic cycloalkylene, a polycyclic arylene, or a polycyclic heteroarylene, and the first atom of the first ring of the polycyclic arylene or heteroarylene is 【Chemical Formula 615】 It is connected to the second atom of the second ring of the polycyclic arylene or heteroarylene, １ Connected to In the formula, L is independent of 0 to 4 R １０ Replaced by, Each R １０ However, independently, = O, halogen, C １－６ Alkyl, C １－６ Alkoxy, S-C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Cycloalkyl, cyano, hydroxy, NH ２ , -NH-C １－６ Alkyl, N(C) １－６ Alkyl) ２ COOH, COC １－６ Alkyl, COOC １－６ Alkyl, CON １－６ Alkyl, CON(C) １－６ Alkyl) ２ NHCOC １－６ Alkyl or heterocyclic, where each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocyclic is independently halogen, cyano, hydroxyl, or NH. ２ , and optionally substituted with 1 to 3 substituents selected from COOH, R １ but, ● 1 to 3 R ｇ 5-12 member carbocyclils that are optionally substituted, ● 1 to 3 R ｇ 6- to 18-membered aryl groups that are optionally substituted, ● A 5-12 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocycline contains 1-3 R ｇ A 5-12 member monocyclic heterocycline is optionally substituted in the following: ● A 5-12 member monocyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heteroaryl contains 1-3 R ｇ 5-12 member monocyclic heteroaryls are optionally substituted. ● A 7-14 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the bicyclic heteroaryl contains 1-4 R ｇ A 7-14 membered bicyclic heteroaryl, which is optionally substituted, or ● A 7-20 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, S, or O, wherein the tricyclic heteroaryl contains 1-5 R ｇ It is a 7-20 member tricyclic heteroaryl that is optionally substituted, Each R ｇ However, independently, hydrogen, SF ５ ,=O, halogen, cyano, hydroxyl, nitro, NH ２ , -COOH, C １－６ Alkyl, C １－６ Alkoxy, C ３－６ Cycloalkyloxy, C ２－６ Alkenyloxy, C ２－６ Alkynyloxy, C ３－６ Cycloalkyl, C ２－６ Alkenil, C ２－５ Alkinyl, -NHC １－６ Alkyl, -N(C) １－６ Alkyl) ２ , -COC １－６ Alkyl, -COOC １－６ Alkyl, -CONH ２ , -CONHC １－６ Alkyl, -CONHC ３－６ Cycloalkyl, -CON(C １－６ Alkyl) ２ , -NHCOC １－６ Alkyl, -NHCOC ３－５ Cycloalkyl, -P(O)(C １－６ Alkyl), -S(O)C １－６ Alkyl, -S(O) ２ C １－６ Alkyl, -S(O) ２ C ３－６ Cycloalkyl, -SO ２ -3- to 7-membered heterocyclyl, -S(O)NH ２ , -S(O)NHC １－６ Alkyl, -S(O)N(C) １－６ Alkyl) ２ , -S(O) ２ NH ２ , -OSO ２ -C １－６ Alkyl, C １－６ Alkylene-OC １－６ Alkyl, C ３－８ - Selected from a 3- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from cycloalkenyloxy, aryl, heteroaryl, N, S, and O, and the R ｇ However, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ -alkylene-OH, -CONH ２ , NH ２ , C １－６ alkoxy, hydroxyl, -COOH, halogen, or one to three groups selected from 5- to 7-membered heterocycles containing one to three heteroatoms selected from N, S, or O, optionally further substituted with one to three groups selected from =O, halogen, cyano, C １－６ alkyl, and C １－６ haloalkyl, and a compound of formula (I), or a pharmaceutically acceptable salt or deuterated form thereof.

2. R ０ is a 5- to 12-membered monocyclic heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, or O, and the monocyclic heterocyclic ring is optionally substituted with 1 to 3 R ８ The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof.

3. R ０ but, 【Chemical 616】 And, X １ and X ２ However, independently, O, S, NH, N(C) １－６ Alkyl), or CR １２ R １３ X １ and X ２ At least one of them is CR １２ R １３ Instead, X ３ However, O, S, NH, or N(C) １－６ It is alkyl, R ８ However, H, halogen, oxo, cyano, hydroxyl, NH ２ NH(C １－６ Alkyl), N (C １－６ Alkyl) ２ COOH, C １－６ Alkyl, C １－６ Alkyl-OH, -CONH ２ , -S(=O)NH ２ , -S(O) ２ NH ２ , C １－６ Alkoxy or C halogenated １－６ It is an alkoxy, R １２ However, H, halogen, cyano, hydroxyl, NH ２ NH(C １－６ Alkyl), N (C １－６ Alkyl) ２ COOH, C １－６ Alkyl, C １－６ Alkyl-OH, -CONH ２ , -S(=O)NH ２ , -S(O) ２ NH ２ , C １－６ Alkoxy or C halogenated １－６ It is an alkoxy, R １３ However, independently, H, halogen, or C １ -C ６ It is alkyl, R Ａ However, H, C １－６ Alkyl, C １－６ Alkilen-carbocykrill, or C １－６ It is an alkylene-heteroaryl, R Ｂ However, C １－６ Alkyl, C ２－６ Alkenil, C １－６ Alkilen-carbocykrill, or C １－６ It is either an alkylene-heteroaryl or R Ａ and R Ｂ However, they come together to form a heterocycline, The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or deuterated form thereof, wherein m is 0, 1, 2, or 3.

4. R ０ but, 【Chemical 617】 The compound according to claim 3, or a pharmaceutically acceptable salt or deuterated form thereof, wherein m is 2 or 3.

5. R ０ but, 【Chemical 618】 And, X １ and X ２ However, independently, O, S, NH, N(C) １－６ Alkyl), or CR １２ R １３ X １ and X ２ At least one of them is CR １２ R １３ Instead, Each R ８ However, independently, H, halogen, oxo, cyano, hydroxyl, NH ２ NH(C １－６ Alkyl), N (C １－６ Alkyl) ２ COOH, C １－６ Alkyl, C １－６ Alkyl-OH, -CONH ２ , -S(=O)NH ２ , -S(O) ２ NH ２ , C １－６ Alkoxy or C halogenated １－６ Selected from alkoxy, R １２ However, H, halogen, C １－６ It is alkyl, Each R １３ However, independently, H, halogen, or C １ -C ６ The compound according to claim 3 or 4, or a pharmaceutically acceptable salt or deuterated form thereof, which is alkyl.

6. R ０ but, 【Chemical 619】 And, X １ and X ２ However, independently, O, S, NH, N(C) １－６ Alkyl), or CR １２ R １３ X １ and X ２ At least one of them is CR １２ R １３ Instead, X ３ However, O, S, NH, or N(C) １－６ It is alkyl, R Ａ However, H, C １－６ Alkyl, C １－６ Alkilen-carbocykrill, or C １－６ It is an alkylene-heteroaryl, R Ｂ However, C １－６ Alkyl, C ２－６ Alkenil, C １－６ Alkilen-carbocykrill, or C １－６ It is either an alkylene-heteroaryl or R Ａ and R Ｂ However, they come together to form a heterocycline, R １２ However, H, halogen, C １－６ It is alkyl, Each R １３ However, independently, H, halogen, or C １ -C ６ The compound according to claim 3, or a pharmaceutically acceptable salt or deuterated form thereof, which is alkyl.

7. R ０ but, 【Chemical Formula 620】 X １ However, O and X ２ However, it is NH, and R ８ However, C １－６ The compound according to claim 5, or a pharmaceutically acceptable salt or deuterated form thereof, which is an alkoxy.

8. R ０ but, 【Chemical 621】 And, Each n1, n2, and n3 is an integer between 0 and 3, and the sum of n1, n2, and n3 is 4 or less. １ and X ２ However, independently, O, S, NR ６ , or CR １２ R １３ X １ and X ２ At least one of them is CR １２ R １３ Instead, each R ６ , R １２ , and R １３ However, independently, H, halo, or C １ -C ６ The compound according to claim 1 or 2, wherein it is alkyl.

9. R ０ but, 【Chemical Formula 622】 And R ８ However, H, F, OH, CH ３ , OCH ３ , OCHF ２ OCF ３ , OCH ２ CH ３ , or -CH ２ OCH ３ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or deuterated form thereof.

10. R ０ but, 【Chemical Formula 623】 The compound according to any one of claims 1 to 4.

11. R ０ However, it is a 5-12 membered polycyclic heterocycle containing 1-3 heteroatoms selected from N, S, and O, and the polycyclic heterocycle contains 1-3 R ８ The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, which is optionally substituted with.

12. R ０ but, ● A 5-12 membered spiroheterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the spiroheterocycle contains 1-3 R ８ A 5- to 12-membered spiroheterocyclic ring, which is optionally substituted by ● A 5-12 membered condensed heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the spiroheterocycle contains 1-3 R ８ A 5- to 12-membered condensed heterocycle, which is optionally substituted by, ● A 7-12 membered bridged heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the bridged heterocycle contains 1-3 R ８ The compound according to claim 1 or 11, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is a 7- to 12-membered crosslinked heterocycle that is optionally substituted.

13. R ０ However, it is a 5-12 membered spiroheterocycle containing 1-3 heteroatoms selected from N, S, or O, and the spiroheterocycle contains 1-3 R ８ A compound according to any one of claims 1, 11, or 12, or a pharmaceutically acceptable salt or deuterated form thereof, which is optionally substituted with.

14. R ０ but, 【Chemical 624】 And, m1 and m2 are independently 0, 1, or 2, provided that neither m1 nor m2 is 0, or neither m1 nor m2 is 2. The compound according to claim 12 or 13, or a pharmaceutically acceptable salt or deuterated form thereof, wherein p is 1 or 2.

15. R ０ but, 【Chemical 625】 The compound according to any one of claims 12 to 14, or a pharmaceutically acceptable salt or deuterated form thereof.

16. R ０ However, it is a 5-12 membered fused heterocycle containing 1-3 heteroatoms selected from N, S, and O, and the fused heterocycle contains 1-3 R ８ The compound according to claim 1, 11, or 12, or a pharmaceutically acceptable salt or deuterated form thereof, which is optionally substituted with.

17. R ０ but, 【Chemical 626】 And, m4 is 0 or 1, m5 is 1 or 2, X ２ is O, S, NH, N(C １－６ Alkyl), or CR １２ R １３ And, R １２ However, H, halogen, cyano, hydroxyl, NH ２ NH(C １－６ Alkyl), N (C １－６ Alkyl) ２ COOH, C １－６ Alkyl, -CONH ２ , -S(=O)NH ２ , -S(O) ２ NH ２ , C １－６ Alkoxy or C halogenated １－６ Selected from alkoxy, R １３ However, independently, H, F, Cl, Br, I, or C １ -C ６ The compound according to claim 16, or a pharmaceutically acceptable salt or deuterated form thereof, which is alkyl.

18. R ０ but, 【Chemical Formula 627】 And, X ２ is O, S, NH, N(C １－６ Alkyl), or CR １２ R １３ And, R １２ However, H, halogen, cyano, hydroxyl, NH ２ NH(C １－６ Alkyl), N (C １－６ Alkyl) ２ COOH, C １－６ Alkyl, -CONH ２ , -S(=O)NH ２ , -S(O) ２ NH ２ , C １－６ Alkoxy or C halogenated １－６ It is an alkoxy, R １３ However, H, halogen or C １ -C ６ It is alkyl, The compound according to claim 16, or a pharmaceutically acceptable salt or deuterated form thereof, wherein each m and m' is independently an integer between 0 and 3, and the sum of m and m' is 3 or less.

19. R ０ but, 【Chemical Formula 628】 The compound according to claim 17, or a pharmaceutically acceptable salt or deuterated form thereof.

20. R ０ but, 【Chemical Formula 629】 And, X ２ is O, S, NH, N(C １－６ Alkyl), or CR １２ R １３ And, R １２ However, H, halogen, C １－６ It is alkyl, R １３ However, H, halogen, or C １ -C ６ It is alkyl, The compound according to claim 12 or 16, or a pharmaceutically acceptable salt or deuterated form thereof, wherein each m and m' is independently an integer between 0 and 3, and the sum of mc and mc' is 3 or less.

21. R ０ but, 【Chemical 630】 X ２ The compound according to claim 20, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is NH, O, or S.

22. R ０ but, 【Chemistry 631】 The compound according to claim 21, or a pharmaceutically acceptable salt or deuterated form thereof.

23. R ０ but, 【Chemical 632】 The compound according to claim 20, or a pharmaceutically acceptable salt or deuterated form thereof.

24. R ０ but, 【Chemical Formula 633】 And, X ２ is O, S, NH, N(C １－６ Alkyl), or CR １２ R １３ And, R １２ However, H, halogen, C １－６ It is alkyl, R １３ However, H, halogen, or C １ -C ６ The compound according to claim 18, or a pharmaceutically acceptable salt or deuterated form thereof, which is alkyl.

25. R ０ but, 【Transformation 634】 The compound according to claim 24, or a pharmaceutically acceptable salt or deuterated form thereof.

26. R ０ However, it is a 7-12 membered bridged heterocycle containing 1-3 heteroatoms selected from N, S, and O, and the bridged heterocycle contains 1-3 R ８ The compound according to claim 11 or 12, or a pharmaceutically acceptable salt or deuterated form thereof, which is optionally substituted with.

27. R ０ but, 【Chemical 635】 And each of these has 1 to 4 R ８ It is optionally replaced by, A is bonded, -O-, -O-CH ２ -ien-CH ２ -O-CH ２ -ien-CH ２ OCH ２ CH ２ -ien-CH ２ -ien-CH ２ CH ２ -, or -CH ２ It is NH-, B is N or CH, I understand ４ However, it is either 0 or 1, p １ However, it is 0, 1, or 2, q １ The compound according to claim 26, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is 1, 2, or 3.

28. R ０ but, 【Chemical 636】 The compound according to claim 26 or 27, or a pharmaceutically acceptable salt or deuterated form thereof.

29. R ０ but, 【Chemical Formula 637】 The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof.

30. R １ However, 1 to 3 R ｇ The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, which is a 5- to 12-membered carbocyclyl optionally substituted with a group.

31. R １ but, 【Chemical Formula 638】 And each of these has 1 to 3 R ｇ The compound according to claim 30, or a pharmaceutically acceptable salt or deuterated form thereof, which is optionally substituted with a group.

32. R １ However, 1 to 3 R ｇ The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is a 6- to 18-membered aryl group optionally substituted with a group.

33. R １ but, 【Chemistry 639】 And in the formula, L is R １ By replacing any hydrogen atom in R １ Each R is coupled １ However, 1 to 3 R ｇ The compound according to claim 32, or a pharmaceutically acceptable salt or deuterated form thereof, which is optionally substituted with.

34. R １ but, 【Chemical 640】 The compound according to claim 32, or a pharmaceutically acceptable salt or deuterated form thereof.

35. R １ but, 【Chemistry 641】 The compound according to claim 34, or a pharmaceutically acceptable salt or deuterated form thereof.

36. R １ but, 【Chemistry 642】 The compound according to claim 34 or 35, or a pharmaceutically acceptable salt or deuterated form thereof.

37. R １ but, 【Chemistry 643】 The compound according to claim 34, or a pharmaceutically acceptable salt or deuterated form thereof.

38. R １ but, 【Chemical Formula 644】 The compound according to claim 37, or a pharmaceutically acceptable salt or deuterated form thereof.

39. R １ However, it is a 5-12 member monocyclic heterocycline containing a heteroatom selected from N, S, or O, and the monocyclic heterocycline contains 1-3 R ｇ The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, which is optionally substituted with a group.

40. R １ but, 【Chemical 645】 And R １ Each of these has 1 to 3 R ｇ The compound according to claim 39, or a pharmaceutically acceptable salt or deuterated form thereof, which is optionally substituted with a group.

41. R １ However, it is a 5- to 12-membered monocyclic heteroaryl containing a heteroatom selected from N, S, or O, and each of the monocyclic heteroaryls contains 1 to 3 R ｇ The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, which is optionally substituted with a group.

42. R １ but, 【Chemical Formula 646】 And each of these has 1 to 3 R ｇ The compound according to claim 41, or a pharmaceutically acceptable salt or deuterated form thereof, which is optionally substituted with a group.

43. Each R ｇ However, independently, H, halogen, C １ -C ６ Alkyl, OSO ２ C １－６ The compound according to claim 41 or 42, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is alkyl or CN.

44. R １ but, 【Transformation 647】 The compound according to claim 42 or 43, or a pharmaceutically acceptable salt or deuterated form thereof.

45. R １ However, it is a 7-14 membered bicyclic heteroaryl containing a heteroatom selected from N, S, or O, and the bicyclic heteroaryl contains 1-4 R ｇ The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, which is optionally substituted with a group.

46. R ｇ However, R ６ or R ７ And, Each R ６ However, independently, H and C １－６ Alkyl, -COC １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl and C ３－６ Selected from cycloalkyls, wherein the alkyl, alkenyl, alkynyl, and cycloalkyls are halogens, cyano, hydroxyl, and NH ２ , and optionally substituted with 1 to 3 groups selected from COOH, Each R ７ However, independently, H, halogen, C １－６ Alkyl, C １－６ Alkoxy, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Cycloalkyl, cyano, hydroxyl, NH ２ NHC １－６ Alkyl, N(C) １－６ Alkyl) ２ COOH, COC １－６ Alkyl, COOC １－６ Alkyl, CONHC １－６ Alkyl, CON(C) １－６ Alkyl) ２ NHCOC １－６ Selected from an alkyl group and a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, or O, R ７ The alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups within are halogen, cyano, hydroxyl, and NH ２ The compound according to claim 1 or 45, or a pharmaceutically acceptable salt or deuterated form thereof, which is optionally substituted with one to three groups selected from COOH.

47. R １ but, 【Chemical 648】 And each of these has 1 to 3 R ｇ The compound according to claim 45, or a pharmaceutically acceptable salt or deuterated form thereof, which is optionally substituted with a group.

48. R １ but, 【Chemical 649】 And in the formula, Y, independently, O, S, CHR ６ , or NR ６ And, R ６ However, by one, two, or three F atoms, or by OH, O-C １－６ Alkyl, N(C) １－６ Alkyl) ２ C, optionally substituted with cycloalkyl or heterocyclyl １－６ The compound according to claim 45 or 46, or a pharmaceutically acceptable salt or deuterated form thereof, which is alkyl.

49. R １ but, 【Chemical 650】 The compound according to claim 48, or a pharmaceutically acceptable salt or deuterated form thereof.

50. R １ but, 【Chemical 651】 And, X ４ However, NR ６ , O, CR ７ CR １４ R １５ , S, S(O), or S(O) ２ And, Q is CH or N, Each R ６ However, independently, H and C １－６ Alkyl, -COC １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl and C ３－６ Selected from cycloalkyls, wherein the alkyl, alkenyl, alkynyl, and cycloalkyls are halogens, cyano, hydroxyl, and NH ２ , and optionally substituted with 1 to 3 groups selected from COOH, Each R ７ However, independently, H, halogen, C １－６ Alkyl, C １－６ Alkoxy, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Cycloalkyl, cyano, hydroxyl, NH ２ NHC １－６ Alkyl, N(C) １－６ Alkyl) ２ COOH, COC １－６ Alkyl, COOC １－６ Alkyl, CONHC １－６ Alkyl, CON(C) １－６ Alkyl) ２ NHCOC １－６ Selected from an alkyl group and a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, or O, R ７ The alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups within are halogen, cyano, hydroxyl, and NH ２ , and optionally substituted with 1 to 3 groups selected from COOH, R １４ and R １５ However, each is independent of H, halogen, and C. １－６ Alkyl, C １－６ Alkoxy, C ２－６ Alkenil, C ２－６ Alkinyl, C ２－６ Alkenyloxy, C ２－６ Alkynyloxy, C ３－６ Cycloalkyl, C ３－６ Cycloalkoxy, cyano, hydroxyl, NH ２ , COOH, -S(O)C １－６ Alkyl, -S(O) ２ C １－６ Alkyl, -S(O) ２ C ３－６ Cycloalkyl, -SO ２ - Selected from 3- to 7-membered heterocyclyls and 4- to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycles are halogens, cyano, hydroxyl, NH ２ , and are optionally substituted with 1 to 3 groups selected from -COOH, Alternatively, R １４ and R １５ However, the compound according to claim 45 or 46, or a pharmaceutically acceptable salt or deuterated form thereof, which forms =O.

51. R １ but, 【Chemical 652】 And, Each X ４ However, it became independent, NR ６ , O, CR １４ R １５ , S, S(O), or S(O) ２ And, Each R ６ However, independently, H and C １－６ Alkyl, -COC １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl and C ３－６ Selected from cycloalkyls, wherein the alkyl, alkenyl, alkynyl, and cycloalkyls are halogens, cyano, hydroxyl, and NH ２ , and optionally substituted with 1 to 3 groups selected from COOH, Each R ７ However, independently, H, halogen, C １－６ Alkyl, C １－６ Alkoxy, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Cycloalkyl, cyano, hydroxyl, NH ２ NHC １－６ Alkyl, N(C) １－６ Alkyl) ２ COOH, COC １－６ Alkyl, COOC １－６ Alkyl, CONHC １－６ Alkyl, CON(C) １－６ Alkyl) ２ NHCOC １－６ Selected from an alkyl group and a 4- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, or O, R ７ The alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups within are halogen, cyano, hydroxyl, and NH ２ , and optionally substituted with 1 to 3 groups selected from COOH, R １４ and R １５ However, each is independent of H, halogen, and C. １－６ Alkyl, C １－６ Alkoxy, C ２－６ Alkenil, C ２－６ Alkinyl, C ２－６ Alkenyloxy, C ２－６ Alkynyloxy, C ３－６ Cycloalkyl, C ３－６ Cycloalkoxy, cyano, hydroxyl, NH ２ , COOH, -S(O)C １－６ Alkyl, -S(O) ２ C １－６ Alkyl, -S(O) ２ C ３－６ Cycloalkyl, -SO ２ - Selected from 3- to 7-membered heterocyclyls and 4- to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycles are halogens, cyano, hydroxyl, NH ２ , and are optionally substituted with 1 to 3 groups selected from -COOH, Alternatively, R １４ and R １５ However, the compound according to claim 45 or 46, or a pharmaceutically acceptable salt or deuterated form thereof, which forms =O.

52. Each X ４ However, independently, O, S, NR ６ , or CR １４ R １５ And, R ６ However, by one, two, or three F atoms, or by OH, O-C １－６ Alkyl, N(C) １－６ Alkyl) ２ C, optionally substituted with cycloalkyl or heterocyclyl １－６ It is alkyl, R ７ However, H, halo, or C １－６ It is alkyl, R １４ and R １５ However, independently, H, halo, or C １－６ The compound according to claim 50, or a pharmaceutically acceptable salt or deuterated form thereof, which is alkyl.

53. Each X ４ However, independently, NH, O, S, CHF, or CHF ２ The compound according to claim 52 or 53, or a pharmaceutically acceptable salt or deuterated form thereof.

54. R １ but, 【Chemical 653】 The compound according to claim 52 or 53, or a pharmaceutically acceptable salt or deuterated form thereof.

55. R １ but, 【Chemical 654】 The compound according to claim 52 or 53, or a pharmaceutically acceptable salt or deuterated form thereof.

56. R １ but, 【Chemical Formula 655】 The compound according to any one of claims 45 to 46 or 51, or a pharmaceutically acceptable salt or deuterated form thereof.

57. R １ but, 【Chemical Formula 656】 The compound according to any one of claims 45-46, 51, or 56, or a pharmaceutically acceptable salt or deuterated form thereof.

58. R １ However, 1 to 4 R ６ or R ７ It is optionally substituted in the base. 【Chemical Formula 657】 The compound according to claim 45 or 46, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the ring C is a 7-8 membered heterocycle comprising 1-3 heteroatoms selected from O, S, and N.

59. R １ but, 【Chemical Formula 658】 And each of these has 1 to 4 R ６ or R ７ The compound according to claim 58, or a pharmaceutically acceptable salt or deuterated form thereof, which is optionally substituted with.

60. R １ but, 【Chemistry 659】 The compound according to claim 58 or 59, or a pharmaceutically acceptable salt or deuterated form thereof.

61. R １ However, it is a 7-20 member tricyclic heteroaryl containing a heteroatom selected from N, S, or O, and the tricyclic heteroaryl contains 1-5 R ｇ It is optionally replaced by R ｇ However, R ６ , R ７ , R １１ , R １４ , or R １５ The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof.

62. R １ However, it is a 7-20 membered spirotricyclic heteroaryl containing a heteroatom selected from N, S, or O, and the tricyclic heteroaryl contains 1-5 R ｇ The compound according to claim 1 or 61, or a pharmaceutically acceptable salt or deuterated form thereof, which is optionally substituted with.

63. R １ but, 【Chemical Formula 660】 And, Each R ６ However, independently, H and C １－６ Alkyl, -COC １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Selected from cycloalkyl or alkylene-O-alkyl, wherein the alkyl, alkenyl, alkynyl, and cycloalkyl are halogen, cyano, hydroxyl, NH ２ , and optionally substituted with 1 to 3 groups selected from COOH, R １４ and R １５ However, each is independent of H, halogen, and C. １－６ Alkyl, C １－６ Alkoxy, C ２－６ Alkenil, C ２－６ Alkinyl, C ２－６ Alkenyloxy, C ２－６ Alkynyloxy, C ３－６ Cycloalkyl, C ３－６ Cycloalkoxy, cyano, hydroxyl, NH ２ , COOH, -S(O)C １－６ Alkyl, -S(O) ２ C １－６ Alkyl, -S(O) ２ C ３－６ Cycloalkyl, -SO ２ - Selected from 3- to 7-membered heterocyclyls and 4- to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycles are halogens, cyano, hydroxyl, NH ２ , and are optionally substituted with 1 to 3 groups selected from -COOH, Alternatively, R １４ and R １５ The compound according to claim 61 or 62, or a pharmaceutically acceptable salt or deuterated form thereof, which forms =O.

64. R １ but, 【Chemical 661】 And in the formula, W, X ４ , and Y ２ However, each is independently CH or N, except W, X ４ , and Y ２ The condition is that at most one of them can be N, DE is N(H)-C(=O), N(C １－６ Alkyl)-C(=O), CH ２ CH ２ , C(=O)-O, or CH ２ -O, R １１ However, H, C １－６ Alkyl, alkylene-O-alkyl, or heterocyclyl, The compound according to claim 62 or 63, or a pharmaceutically acceptable salt or deuterated form thereof, wherein i and j are each independently 1, 2, or 3, provided that the sum of i + j is 2, 3, or 4.

65. R １ but, 【Chemical 662】 The compound according to any one of claims 61 to 64, or a pharmaceutically acceptable salt or deuterated form thereof.

66. R １ but, 【Chemical Formula 663】 The compound according to any one of claims 61 to 65, or a pharmaceutically acceptable salt or deuterated form thereof.

67. R １ However, it is a 7-20 membered condensed tricyclic heteroaryl containing a heteroatom selected from N, S, or O, and the tricyclic heteroaryl contains 1-5 R ｇ The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, which is optionally substituted with.

68. R １ However, 1 to 5 R ｇ Replaced by any choice 【Chemical Formula 664】 And in the formula, X ５ and X ６ However, each is independent of the single bond, -C(R) １４ R １５ )-O-,-C(R １４ R １５ )-C(R １４ R １５ )-,-OC(R １４ R １５ )-,-C(R １４ R １５ )-, -O-, and -NR ６ - Selected from, R １４ and R １５ However, each is independent of H, halogen, and C. １－６ Alkyl, C １－６ Alkoxy, C ２－６ Alkenil, C ２－６ Alkinyl, C ２－６ Alkenyloxy, C ２－６ Alkynyloxy, C ３－６ Cycloalkyl, C ３－６ Cycloalkoxy, cyano, hydroxyl, NH ２ , COOH, -S(O)C １－６ Alkyl, -S(O) ２ C １－６ Alkyl, -S(O) ２ C ３－６ Cycloalkyl, -SO ２ - Selected from 3- to 7-membered heterocyclyls and 4- to 7-membered heterocycles containing 1 to 3 heteroatoms selected from N, S, or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycles are halogens, cyano, hydroxyl, NH ２ , and are optionally substituted with 1 to 3 groups selected from -COOH, Each R ６ However, independently, H and C １－６ Alkyl, -COC １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Selected from cycloalkyl or alkylene-O-alkyl, wherein the alkyl, alkenyl, alkynyl, and cycloalkyl are halogen, cyano, hydroxyl, NH ２ , and optionally substituted with 1 to 3 groups selected from COOH, Ring D is selected from a 5-8 membered heteroaryl containing an aryl and 1-3 heteroatoms, and each of the 5-8 membered heteroaryls containing an aryl and 1-3 heteroatoms independently contains 1-3 R ｇ It is optionally replaced, However, if ring D is aryl, X ５ and X ６ Both of them are -C(R １４ R １５ )-C(R １４ R １５ ) - or - C (R １４ R １５ ) - The compound according to claim 1 or 67, or a pharmaceutically acceptable salt or deuterated form thereof, provided that it is not -

69. R １ but, 【Chemical Formula 665】 And each of these has 1 to 5 R ｇ The compound according to claim 68, or a pharmaceutically acceptable salt or deuterated form thereof, which is optionally substituted with a group.

70. Ring D is 【Chemical 666】 And each of these has 1 to 3 R ｇ The compound according to claim 68 or 69, or a pharmaceutically acceptable salt or deuterated form thereof, which is optionally substituted with a group.

71. R １ but, 【Chemical Formula 667】 The compound according to any one of claims 68 to 70, or a pharmaceutically acceptable salt or deuterated form thereof.

72. A compound according to any one of claims 1 to 71, or a pharmaceutically acceptable salt or deuterated form thereof, wherein L is a polycyclic cycloalkylene.

73. The compound according to any one of claims 1 to 72, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the polycyclic cycloalkylene comprises 4 to 10 carbon atoms.

74. The polycyclic cycloalkylene is the first quaternary carbon of the polycyclic cycloalkylene, R １ It is connected to the second quaternary carbon of the polycyclic cycloalkylene via the second quaternary carbon of the polycyclic cycloalkylene. 【Chemical 668】 A compound according to any one of claims 1 to 73, or a pharmaceutically acceptable salt or deuterated form thereof, independently connected to the above.

75. The aforementioned polycyclic cycloalkylene, 【Chemical 669】 The compound according to any one of claims 1 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

76. The aforementioned polycyclic cycloalkylene, 【Chemical 670】 The compound according to any one of claims 1 to 75, or a pharmaceutically acceptable salt or deuterated form thereof.

77. L has 0 to 4 R １０ A compound according to any one of claims 1 to 76, or a pharmaceutically acceptable salt or deuterated form thereof, which is a polycyclic heteroarylene substituted by.

78. The aforementioned polycyclic heteroarylene contains 8 to 12 ring atoms and 0 to 4 R １０ The compound according to claim 77, or a pharmaceutically acceptable salt or deuterated form thereof, which is substituted by.

79. The aforementioned polycyclic heteroarylene contains 8 to 10 ring atoms and 0 to 4 R １０ The compound according to claim 77 or 78, or a pharmaceutically acceptable salt or deuterated form thereof, substituted by.

80. The aforementioned polycyclic heteroarylene contains 8 to 9 ring atoms and 0 to 4 R １０ A compound according to any one of claims 77 to 79, or a pharmaceutically acceptable salt or deuterated form thereof, substituted by.

81. The aforementioned polycyclic heteroarylene has 0 to 4 R １０ Replaced by 【Chemistry 671】 The compound according to claim 77, or a pharmaceutically acceptable salt or deuterated form thereof, wherein ring B is a heteroaryl ring.

82. The polycyclic heteroarylene comprises nine ring atoms selected from O, N, or S and one or two heteroatoms, and the polycyclic heteroarylene contains 0 to 4 R １０ A compound according to any one of claims 77 to 81, or a pharmaceutically acceptable salt or deuterated form thereof, substituted by.

83. The aforementioned polycyclic heteroarylene has 0 to 4 R １０ Replaced by 【Transformation 672】 In the formula, X' is O, S, NH, or N(C) １－６ A compound according to any one of claims 77 to 82, which is alkyl, or a pharmaceutically acceptable salt or deuterated form thereof.

84. The aforementioned polycyclic heteroarylene has 0 to 4 R １０ A compound according to any one of claims 77 to 83, or a pharmaceutically acceptable salt or deuterated form thereof, which is benzothienylene, indolylene, or benzofuranylene substituted by .

85. The aforementioned polycyclic heteroarylene, 【Chemistry 673】 And each of these has 0 to 4 R １０ A compound according to any one of claims 77 to 84, or a pharmaceutically acceptable salt or deuterated form thereof, substituted by. 【Request Item 86】 【Chemistry 674】 but, 【Chemistry 675】 Bonded to the phenyl ring, R １ but, 【Chemical Formula 676】 Bonded to the five-membered ring, in the formula, 【Chemical 677】 However, there are 0 to 4 R １０ The compound according to claim 85, or a pharmaceutically acceptable salt or deuterated form thereof, substituted by. 【Request Item 87】 【Transformation 678】 but, 【Transformation 679】 Bonded to the 5-membered ring, R １ but, 【Chemical 680】 Bonded to the phenyl ring, in the formula, 【Chemistry 681】 However, there are 0 to 4 R １０ The compound according to claim 85, or a pharmaceutically acceptable salt or deuterated form thereof, substituted by.

88. The aforementioned polycyclic heteroarylene, 【Chemical Formula 682】 The compound according to any one of claims 77 to 87, or a pharmaceutically acceptable salt or deuterated form thereof.

89. The aforementioned polycyclic heteroarylene, 【Chemical Formula 683】 The compound according to any one of claims 77 to 88, or a pharmaceutically acceptable salt or deuterated form thereof.

90. L has 1 to 4 R １０ Replaced by 【Chemical Formula 684】 The compound according to any one of claims 77 to 87, or a pharmaceutically acceptable salt or deuterated form thereof.

91. L is one R １０ Replaced by 【Chemical Formula 685】 The compound according to claim 90, or a pharmaceutically acceptable salt or deuterated form thereof.

92. R １０ The compound according to claim 90 or 91, or a pharmaceutically acceptable salt or deuterated form thereof, which is a halo.

93. L, 【Chemical 686】 The compound according to any one of claims 90 to 92, or a pharmaceutically acceptable salt or deuterated form thereof.

94. L, 【Chemical Formula 687】 The compound according to any one of claims 90 to 93, or a pharmaceutically acceptable salt or deuterated form thereof.

95. The polycyclic heteroarylene comprises eight ring atoms selected from O, N, or S and one or two heteroatoms, and the polycyclic heteroarylene contains 0 to 4 R １０ A compound according to any one of claims 77 to 80, or a pharmaceutically acceptable salt or deuterated form thereof, substituted by.

96. The aforementioned polycyclic heteroarylene, 【Chemical 688】 The compound according to any one of claims 77 to 80 or 95, wherein each of rings E and F is a five-membered heteroaryl or five-membered heterocycline comprising one to three heteroatoms selected from O, N, or S, or a pharmaceutically acceptable salt or deuterated form thereof.

97. The aforementioned polycyclic heteroarylene, 【Chemical Formula 689】 The compound according to any one of claims 77-80 or 95-96, or a pharmaceutically acceptable salt or deuterated form thereof, wherein each of rings E and F is a five-membered heteroaryl comprising one to three heteroatoms selected from O, N, or S.

98. The aforementioned polycyclic heteroarylene, 【Chemical 690】 The compound according to any one of claims 77 to 80 or 95 to 96, or a pharmaceutically acceptable salt or deuterated form thereof.

99. The aforementioned polycyclic heteroarylene, 【Chemistry 691】 The compound according to any one of claims 77-80, 95-96, or 98, or a pharmaceutically acceptable salt or deuterated form thereof.

100. A compound according to any one of claims 1 to 71, or a pharmaceutically acceptable salt or deuterated form thereof, wherein L is a polycyclic arylene.

101. L, 【Chemistry 692】 The compound according to claim 100, or a pharmaceutically acceptable salt or deuterated form thereof.

102. L, 【Chemistry 693】 The compound according to claim 100 or 101, or a pharmaceutically acceptable salt or deuterated form thereof.

103. The aforementioned compound is a compound of formula (II), 【Chemical 694】 The compound according to any one of claims 1 to 71, or a pharmaceutically acceptable salt or deuterated form thereof.

104. The aforementioned compound is a compound of formula (III), 【Chemical 695】 The compound according to any one of claims 1 to 71, or a pharmaceutically acceptable salt or deuterated form thereof.

105. The aforementioned compound is a compound of formula (IV), 【Chemistry 696-1】 The compound according to any one of claims 1 to 71, or a pharmaceutically acceptable salt or deuterated form thereof.

106. The aforementioned compound is a compound of formula (V), 【Chemistry 696-2】 or a pharmaceutically acceptable salt or deuterated form thereof, In the formula, n is 0 or 1, and R １０ The compound according to claim 1, wherein the compound is substituted on the phenyl ring or thiophenyl ring of the benzothienylene ring.

107. The aforementioned compound is a compound of formula (VI), 【Transformation 697】 or a pharmaceutically acceptable salt or deuterated form thereof, In the formula, n is 0 or 1, and R １０ The compound according to claim 1, wherein the compound is substituted on the phenyl ring or thiophenyl ring of the benzothienylene ring.

108. The aforementioned compound is a compound of formula (VII), 【Chemical Formula 698】 or a pharmaceutically acceptable salt or deuterated form thereof, In the formula, n is 0 or 1, and R １０ The compound according to claim 1, wherein the benzothienylene ring may be substituted on the phenyl ring or thiophenyl ring.

109. A compound according to any one of claims 103 to 108, or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0.

110. n is 1, R １０ The compound according to any one of claims 103 to 108, or a pharmaceutically acceptable salt or deuterated form thereof, which is a halo.

111. n is 1, R １０ However, F is the compound according to any one of claims 103 to 108 or 110, or a pharmaceutically acceptable salt or deuterated form thereof.

112. R １ but, 【Chemical Formula 699】 And, X is O, S, or CF ２ And, Y is either O or S, Q is CH or N, R ６ However, C １－３ Alkyl, and the C １－３ Alkyl groups: one, two, or three F, OH, OC １ -3 alkyl, N(C １－３ Alkyl) ２ , optionally substituted with cyclopropyl or tetrahydropyran, R ７ However, H, F, Cl, or CH ３ The compound according to any one of claims 1 to 111, or a pharmaceutically acceptable salt or deuterated form thereof.

113. R １ but, 【Chemical 700】 And, X is O, S, or CF ２ And, Y is either O or S, R ６ However, C １－３ Alkyl, and the C １－３ Alkyl groups: one, two, or three F, OH, OC １－３ Alkyl, N(C) １－３ Alkyl) ２ , optionally substituted with cyclopropyl or tetrahydropyran, R ７ However, H, F, Cl, or CH ３ The compound according to any one of claims 1 to 112, or a pharmaceutically acceptable salt or deuterated form thereof.

114. R １ but, 【Chemical 701】 The compound according to any one of claims 1 to 112, or a pharmaceutically acceptable salt or deuterated form thereof.

115. X is O, R ６ However, C １－３ It is alkyl, R ７ The compound according to claim 114, or a pharmaceutically acceptable salt or deuterated form thereof, wherein H is present.

116. R １ but, 【Chemical 702】 And, X is O, R ６ However, C １－３ Alkyl, and the C １－３ The alkyl group is optionally substituted with one, two, or three F atoms. R ７ The compound according to any one of claims 1 to 112, or a pharmaceutically acceptable salt or deuterated form thereof, wherein H is present.

117. R １ but, 【Chemical 703】 And, X is O, R ６ However, C １－３ It is alkyl, R ７ The compound according to any one of claims 1 to 112, or a pharmaceutically acceptable salt or deuterated form thereof, wherein H is present.

118. R １ but, 【Chemical 704】 A compound according to any one of claims 1 to 112, or a pharmaceutically acceptable salt thereof.

119. R １ but, 【Chemical 705】 The compound according to any one of claims 1 to 112, or a pharmaceutically acceptable salt or deuterated form thereof.

120. R １ but, 【Chemical 706】 The compound according to any one of claims 1 to 112, or a pharmaceutically acceptable salt or deuterated form thereof.

121. R ６ The compound according to any one of claims 105 to 120, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is methyl.

122. R ６ The compound according to any one of claims 105 to 120, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is ethyl.

123. R ６ The compound according to any one of claims 105 to 120, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is propyl.

124. R １ but, 【Chemical 707】 The compound according to any one of claims 1 to 112, or a pharmaceutically acceptable salt or deuterated form thereof.

125. R １ but, 【Chemical 708】 The compound according to any one of claims 1 to 112, or a pharmaceutically acceptable salt or deuterated form thereof.

126. R １ but, 【Chemical 709】 The compound according to any one of claims 1 to 112, or a pharmaceutically acceptable salt or deuterated form thereof.

127. The aforementioned compound is a compound of formula (VIII), 【Chemical Formula 710】 The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof.

128. The aforementioned compound is a compound of formula (IX), 【Chem.711】 The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof.

129. The aforementioned compound is a compound of formula (X), 【Chemical 712】 The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof.

130. The aforementioned compound is a compound of formula (XI), 【Chemical Formula 713】 or a pharmaceutically acceptable salt or deuterated form thereof, During the ceremony, n is 0 or 1, R １０ The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the benzothienylene ring can be substituted on the phenyl or thiophenyl ring.

131. The aforementioned compound is a compound of formula (XII), 【Chemical 714】 or a pharmaceutically acceptable salt or deuterated form thereof, During the ceremony, n is 0 or 1, R １０ The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the benzothienylene ring can be substituted on the phenyl or thiophenyl ring.

132. The aforementioned compound is a compound of formula (XIII), 【Chemical Formula 715】 or a pharmaceutically acceptable salt or deuterated form thereof, During the ceremony, n is 0 or 1, R １０ The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the benzothienylene ring can be substituted on the phenyl or thiophenyl ring.

133. The aforementioned compound is a compound of formula (XVI), 【Chemical 716】 or a pharmaceutically acceptable salt or deuterated form thereof, During the ceremony, Each of rings E and F is either a five-membered heteroarylene or a five-membered heterocyclylene. n is 0 or 1, R １０ The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is substituted on ring E or ring F. 【Request Item 134】 【Chemistry 717】 but, 【Chemical 718】 The compound according to claim 133. 【Request Item 135】 【Chemistry 719】 but, 【Chemical 720】 The compound according to claim 133 or 134.

136. R １０ The compound according to any one of claims 133 to 135, wherein the compound is a halo.

137. The aforementioned compound is a compound of formula (XVII), 【Chem.721】 or a pharmaceutically acceptable salt or deuterated form thereof, During the ceremony, X' is O, S, NH, or N(C) １－６ It is alkyl, n is 0 or 1, R １０ but, 【Chemical 722】 The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is substituted on a phenyl ring or a five-membered ring.

138. The aforementioned compound is a compound of formula (XVIII), 【Chemical Formula 723】 or a pharmaceutically acceptable salt or deuterated form thereof, During the ceremony, X' is O, S, NH, or N(C) １－６ It is alkyl, n is 0 or 1, R １０ but, 【Chemical 724】 The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is substituted on a phenyl ring or a five-membered ring.

139. A compound according to any one of claims 120 to 138, or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0.

140. n is 1, R １０ A compound according to any one of claims 120 to 138, or a pharmaceutically acceptable salt or deuterated form thereof, which is a halo.

141. n is 1, R １０ However, F is the compound according to any one of claims 120 to 138 or 140, or a pharmaceutically acceptable salt or deuterated form thereof.

142. A compound according to any one of claims 127 to 141, or a pharmaceutically acceptable salt or deuterated form thereof, wherein X is O.

143. R ６ However, C １－３ A compound according to any one of claims 127 to 142, which is alkyl, or a pharmaceutically acceptable salt or deuterated form thereof.

144. R ７ The compound according to any one of claims 127 to 143, or a pharmaceutically acceptable salt or deuterated form thereof, wherein H is present.

145. X is O, R ６ However, C １－３ It is alkyl, R ７ The compound according to any one of claims 127 to 144, or a pharmaceutically acceptable salt or deuterated form thereof, wherein H is present.

146. R ０ but, 【Chemical 725】 The compound according to any one of claims 1 to 145, or a pharmaceutically acceptable salt or deuterated form thereof.

147. R ０ but, 【Chemical 726】 The compound according to any one of claims 1 to 146, or a pharmaceutically acceptable salt or deuterated form thereof.

148. R ８ The compound according to claim 146 or 147, wherein H is present.

149. R ０ but, 【Chemical 727】 The compound according to any one of claims 1 to 145, or a pharmaceutically acceptable salt or deuterated form thereof.

150. R ０ but, 【Chemical 728】 The compound according to any one of claims 1 to 145 or 149, or a pharmaceutically acceptable salt or deuterated form thereof.

151. R ０ but, 【Chemical 729】 The compound according to claim 150, or a pharmaceutically acceptable salt or deuterated form thereof.

152. R ０ but, 【Chemical 730】 And in the formula, each R ８ However, independently, H, halogen, oxo, cyano, hydroxyl, NH ２ NH(C １－６ Alkyl), N (C １－６ Alkyl) ２ COOH, C １－６ Alkyl, C １－６ Alkyl-OH, -CONH ２ , -S(=O)NH ２ , -S(O) ２ NH ２ , C １－６ Alkoxy or C halogenated １－６ A compound according to claim 150 or 151, selected from alkoxys, or a pharmaceutically acceptable salt or deuterated form thereof.

153. R ０ but, 【Chemistry 731】 And in the formula, each R ８ However, independently, H, halogen, C １－６ Alkyl, C １－６ Alkoxy or C halogenated １－６ A compound according to any one of claims 150 to 152, selected from alkoxys, or a pharmaceutically acceptable salt or deuterated form thereof.

154. R ０ but, 【Chemical 732】 The compound according to claim 150, or a pharmaceutically acceptable salt or deuterated form thereof.

155. R ０ but, 【Chemical 733】 The compound according to claim 150, or a pharmaceutically acceptable salt or deuterated form thereof.

156. R ０ but, 【Chemistry 734】 The compound according to claim 150, or a pharmaceutically acceptable salt or deuterated form thereof.

157. at least one R ８ The compound according to any one of claims 1 or 149 to 156, wherein H is present, or a pharmaceutically acceptable salt or deuterated form thereof.

158. at least one R ８ The compound according to any one of claims 1 or 149 to 156, wherein the compound is methoxy, or a pharmaceutically acceptable salt or deuterated form thereof.

159. at least one R ８ The compound according to claim 1 or any one of claims 149 to 156, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is ethoxy.

160. at least one R ８ The compound according to claim 1 or any one of claims 149 to 156, wherein the compound is an OH group, or a pharmaceutically acceptable salt or deuterated form thereof.

161. R ０ but, 【Chemical 735】 The compound according to any one of claims 1 to 148, or a pharmaceutically acceptable salt or deuterated form thereof.

162. R ０ but, 【Chemical 736】 The compound according to any one of claims 1 to 148 or 161, or a pharmaceutically acceptable salt or deuterated form thereof.

163. R ０ but, 【Chemical 737】 The compound according to any one of claims 1 to 148 or 161, or a pharmaceutically acceptable salt or deuterated form thereof.

164. R ０ but, 【Chemical 738】 The compound according to claim 149 or 150, or a pharmaceutically acceptable salt or deuterated form thereof.

165. R ０ but, 【Chemical 739】 The compound according to any one of claims 149 to 153 or 164, or a pharmaceutically acceptable salt or deuterated form thereof.

166. R ０ but, 【Chemical 740】 The compound according to any one of claims 149 to 153 or 164 to 165, or a pharmaceutically acceptable salt or deuterated form thereof.

167. R ０ but, 【Chemistry 741】 The compound according to any one of claims 149 to 153 or 164 to 165, or a pharmaceutically acceptable salt or deuterated form thereof.

168. R ０ but, 【Chemistry 742】 The compound according to any one of claims 149 to 153 or 164 to 165, or a pharmaceutically acceptable salt or deuterated form thereof.

169. R ０ but, 【Chemical 743】 The compound according to claim 164, or a pharmaceutically acceptable salt or deuterated form thereof.

170. R ０ but, 【Chemical 744】 The compound according to claim 164, or a pharmaceutically acceptable salt or deuterated form thereof.

171. R ０ but, 【Chem.745】 The compound according to claim 164, or a pharmaceutically acceptable salt or deuterated form thereof.

172. R ０ but, 【Chemical 746】 The compound according to any one of claims 1 to 145 or 149, or a pharmaceutically acceptable salt or deuterated form thereof.

173. R ０ but, 【Chemical 747】 The compound according to claim 172, or a pharmaceutically acceptable salt or deuterated form thereof.

174. R Ａ However, H or C １－６ A compound according to any one of claims 149 or 172-173, which is alkyl, or a pharmaceutically acceptable salt or deuterated form thereof.

175. R Ａ The compound according to claim 174, or a pharmaceutically acceptable salt or deuterated form thereof, wherein H is present.

176. R Ａ The compound according to claim 174, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is methyl.

177. R Ｂ However, C １－６ Alkyl, C ２－６ Alkenil, C １－６ Alkilen-carbocykrill, or C １－６ A compound according to any one of claims 149 or 172 to 176, which is an alkylene heteroaryl, or a pharmaceutically acceptable salt or deuterated form thereof.

178. R Ｂ However, C １－６ Alkyl, C １－６ Alkylene-aryl, or -C １－６ The compound according to claim 177, which is an alkylene-5 to 6-membered heteroaryl, or a pharmaceutically acceptable salt or deuterated form thereof.

179. R ０ but, 【Chemical 748】 The compound according to claim 172 or 173, or a pharmaceutically acceptable salt or deuterated form thereof.

180. R ０ but, 【Chemical 749】 The compound according to claim 172 or 173, or a pharmaceutically acceptable salt or deuterated form thereof.

181. R ０ but, 【Chemical 750】 The compound according to claim 172 or 173, or a pharmaceutically acceptable salt or deuterated form thereof.

182. R Ｂ The compound according to any one of claims 177 to 181, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is methyl.

183. R Ｂ The compound according to any one of claims 177 to 181, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is ethyl.

184. R Ｂ The compound according to any one of claims 177 to 181, wherein H is present.

185. R ０ but, 【Chemistry 751】 The compound according to claim 180, or a pharmaceutically acceptable salt or deuterated form thereof.

186. R ０ but, 【Chem.752】 The compound according to claim 181, or a pharmaceutically acceptable salt or deuterated form thereof.

187. R ０ but, 【Chemical 753】 The compound according to claim 182, or a pharmaceutically acceptable salt or deuterated form thereof.

188. R Ｂ The compound according to any one of claims 185 to 187, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is methyl.

189. R Ｂ The compound according to any one of claims 185 to 187, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is ethyl.

190. X ３ The compound according to any one of claims 172 to 178, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is O.

191. R ０ but, 【Chem.754】 The compound according to any one of claims 1 to 145, or a pharmaceutically acceptable salt or deuterated form thereof.

192. R ６ However, C １－３ A compound according to any one of claims 127 to 191, which is alkyl, or a pharmaceutically acceptable salt or deuterated form thereof.

193. R ６ However, CH ３ The compound according to claim 192, or a pharmaceutically acceptable salt or deuterated form thereof.

194. R ７ The compound according to any one of claims 127 to 193, or a pharmaceutically acceptable salt or deuterated form thereof, wherein H is present.

195. R １０ The compound according to any one of claims 127 to 194, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is -H or -F.

196. The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is selected from Table 1.

197. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 196, or a pharmaceutically acceptable salt or deuterated form thereof, and a pharmaceutically acceptable adjuvant, diluent, or carrier.

198. A method for treating an obstructive airway disorder in a patient requiring treatment for such disorder, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 196, or a composition according to claim 197.

199. The method according to claim 198, wherein the obstructive airway disease is asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, cystic fibrosis (CF), bronchiectasis, sarcoidosis, alpha-1 antitrypsin (A1AT) deficiency, farmer's lung and related diseases, hypersensitivity pneumonitis, pulmonary fibrosis, complications of lung transplantation, vascular and thrombotic disorders of the pulmonary vascular system, pulmonary hypertension, antitussive effects including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, acute and chronic rhinitis including iatrogenic cough, drug-induced rhinitis and vasomotor rhinitis; perennial and seasonal allergic rhinitis (hay fever) including neurogenic rhinitis, nasal polyps; acute viral infections including the common cold, and infections caused by respiratory viruses, acute lung injury, or acute respiratory distress syndrome (ARDS).

200. The method according to claim 199, wherein the obstructive airway disease is asthma.

201. The method according to claim 199, wherein the obstructive airway disorder is acute respiratory distress syndrome (ARDS).

202. The method according to claim 199, wherein the obstructive airway disease is bronchitis.

203. The method according to claim 199, wherein the obstructive airway disease is pulmonary fibrosis.

204. The method according to claim 199, wherein the obstructive airway disease is emphysema.

205. The method according to claim 199, wherein the obstructive airway disease is cystic fibrosis (CF).

206. The method according to claim 199, wherein the obstructive airway disease is bronchiectasis.

207. The method according to claim 199, wherein the obstructive airway disease is sarcoidosis.

208. The method according to claim 199, wherein the obstructive airway disorder is alpha-1 antitrypsin (A1AT) deficiency.

209. The method according to claim 199, wherein the obstructive airway disease is farmer's lung.

210. The method according to claim 199, wherein the obstructive airway disease is hypersensitivity pneumonitis.

211. The method according to claim 199, wherein the obstructive airway disease is a complication of lung transplantation.

212. The method according to claim 199, wherein the obstructive airway disease is vasculitis or thrombotic disorder of the pulmonary blood vessels.

213. The method according to claim 199, wherein the obstructive airway disease is pulmonary hypertension.

214. The method according to claim 199, wherein the obstructive airway disorder is iatrogenic cough.

215. The method according to claim 199, wherein the obstructive airway disease is acute rhinitis.

216. The method according to claim 199, wherein the obstructive airway disease is chronic rhinitis.

217. The method according to claim 199, wherein the obstructive airway disorder is drug-induced rhinitis or vasomotor rhinitis.

218. The method according to claim 199, wherein the obstructive airway disease is a nasal polyp.

219. The method according to claim 199, wherein the obstructive airway disease is COPD.

220. The method according to claim 200, wherein the asthma is bronchial asthma, allergic asthma, endogenous asthma, exogenous asthma, exercise-induced asthma, or drug-induced asthma.

221. The method according to claim 200, wherein the bronchitis is infectious bronchitis or eosinophilic bronchitis.

222. The method according to claim 203, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis, fibrotic alveolitis of unknown cause, idiopathic interstitial pneumonia, or fibrosis associated with antitumor therapy or chronic infection.

223. The method according to claim 206, wherein the bronchiectasis is noncystic fibrotic bronchiectasis (NCFBE).

224. The method according to claim 206, wherein the bronchiectasis is related to cystic fi25.

225. The method according to claim 213, wherein the pulmonary hypertension is pulmonary artery hypertension.

226. The method according to claim 213, wherein the pulmonary hypertension is pulmonary hypertension caused by left heart disease.

227. The method according to claim 213, wherein the pulmonary hypertension is pulmonary hypertension associated with chronic lung disease.

228. A method for treating cystic fibrosis in a patient requiring treatment for cystic fibrosis, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 196, or a composition according to claim 197.

229. The method according to claim 228, wherein the treatment includes improving the lung function of the patient compared to the lung function of the patient before treatment.

230. Improving the lung function of the patient is achieved by comparing the patient's forced expiratory volume per second (FEV) with the patient's values ​​before treatment. １ To increase the patient's forced vital capacity (FVC), to increase the patient's maximum expiratory flow rate (PEFR), or to increase the patient's forced expiratory flow rate (FEF) to 25% to 75% of the patient's FVC. （２５～７５％） The method according to claim 229, which includes increasing ).

231. The method according to claim 229 or 230, wherein the lung function is measured by vital capacity measurement.

232. A method for treating bronchiectasis in a patient requiring treatment for bronchiectasis, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 196, or a composition according to claim 197.

233. The method according to claim 232, wherein the bronchiectasis is noncystic fibrotic bronchiectasis (NCFBE).

234. The method according to claim 232, wherein the bronchiectasis is related to cystic fibrosis.

235. The method according to any one of claims 232 to 234, wherein the treatment includes improving the lung function of the patient compared to the lung function of the patient before treatment.

236. Improving the lung function of the patient is achieved by comparing the patient's forced expiratory volume per second (FEV) with the patient's values ​​before treatment. １ To increase the patient's forced vital capacity (FVC), to increase the patient's maximum expiratory flow rate (PEFR), or to increase the patient's forced expiratory flow rate (FEF) to 25% to 75% of the patient's FVC. （２５～７５％） The method according to claim 235, which includes increasing ).

237. The method according to claim 235 or 236, wherein the lung function is measured by vital capacity measurement.

238. The method according to any one of claims 232 to 234, wherein the treatment comprises reducing the rate of lung exacerbation compared to the rate of lung exacerbation in the patient before treatment.

239. The method according to any one of claims 232 to 238, wherein the treatment includes increasing the time to the first lung exacerbation compared to untreated patients.

240. The method according to claim 238 or 239, wherein the lung exacerbation is characterized by three or more of the following symptoms, which are exhibited by the patient for at least 48 hours: (1) increased cough, (2) increased sputum volume or change in sputum viscosity, (3) increased sputum purulence, (4) increased shortness of breath and / or decreased exercise tolerance, (5) fatigue and / or malaise, and (6) hemoptysis.

241. A method for treating chronic sinusitis (CRS) in a patient requiring treatment for the chronic sinusitis (CRS), comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 196, or a composition according to claim 197.

242. The method according to claim 241, wherein the chronic sinusitis is chronic sinusitis without nasal polyps (CRSsNP).

243. The method according to claim 241, wherein the chronic sinusitis is chronic sinusitis with nasal polyps (CRSwNP).

244. The method according to claim 241 or 242, wherein the chronic sinusitis is intractable chronic sinusitis.

245. The method according to any one of claims 241 to 244, wherein treatment comprises reducing one or more symptoms of CRS, decreasing their severity, delaying their onset, or eliminating them.

246. The method according to claim 245, wherein one or more of the symptoms of CRS are nasal congestion, nasal obstruction, runny nose, postnasal drip, facial pressure, facial pain, facial bloating, decreased sense of smell, depression, mucosal edema, mucopurulent discharge, middle meatus obstruction, mucosal changes in the natural opening of the middle meatus and in the sinuses, or rhinorrhea.

247. A method for treating a sweat gland abscess (HS) in a patient requiring treatment for the HS, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 196, or a composition according to claim 197.

248. The method according to claim 247, wherein the sweat gland abscess (HS) is stage I of Harley's disease.

249. The method according to claim 247, wherein the sweat gland abscess (HS) is stage II of Harley's disease.

250. The method according to claim 247, wherein the sweat gland abscess (HS) is stage III of Harley's disease.

251. A method for treating cancer in a patient requiring cancer treatment, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 196, or a composition according to claim 197.

252. The method according to claim 251, wherein the cancer is metastatic cancer.

253. The method according to claim 252, wherein the metastatic cancer is metastatic cancer from the breast to the lungs.

254. The method according to claim 252, wherein the metastatic cancer includes metastases of breast cancer to the brain, bones, pancreas, lymph nodes, or liver.

255. The method according to claim 252, wherein the metastatic cancer includes metastasis of bone cancer to the lungs.

256. The method according to claim 252, wherein the metastatic cancer includes metastases of colorectal cancer to the peritoneum, pancreas, stomach, lungs, liver, kidneys, or spleen.

257. The method according to claim 252, wherein the metastatic cancer includes metastases of gastric cancer to the mesentery, spleen, pancreas, lungs, liver, adrenal gland, or ovary.

258. The method according to claim 252, wherein the metastatic cancer includes metastases of liver cancer to the intestines, spleen, pancreas, stomach, lungs, or kidneys.

259. The method according to claim 252, wherein the metastatic cancer includes metastases of lymphoma to the kidneys, ovaries, liver, bladder, or spleen.

260. A method for treating lupus nephritis in a patient requiring treatment for lupus nephritis, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 196, or a composition according to claim 197.

261. A method for treating rheumatoid arthritis in a patient requiring treatment for rheumatoid arthritis, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 196, or a composition according to claim 197.

262. A method for treating inflammatory bowel disease (IBD) in a patient requiring treatment for IBD, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 196 or a composition according to claim 197.

263. The method according to claim 262, wherein the inflammatory bowel disease (IBD) is Crohn's disease.

264. The method according to claim 262, wherein the inflammatory bowel disease (IBD) is ulcerative colitis.

265. A method for treating anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis in a patient requiring treatment for the condition, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 196 or a composition according to claim 197.

266. The method according to claim 265, wherein the ANCA-related disease is granulomatous disease with polyangiitis (GPA).

267. The method according to claim 265, wherein the ANCA-related disease is microscopic polyangiitis (MPA).

268. A method for treating a disease in a patient requiring treatment for the disease, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 196 or a composition according to claim 197, wherein the disease is giant cell arteritis, polyarteritis nodosa, anti-GBM disease (Goodpasture disease), systemic sclerosis, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic ulcer, Duchenne muscular dystrophy, bronchiolitis obliterans, atopic dermatitis, pyoderma gangrenosum, Sweet's syndrome, dermatomyositis / polymyositis, neutrophilic dermatopathies, thrombosis, bronchopulmonary dysplasia, amyotrophic lateral sclerosis, sickle cell anemia, psoriasis, or ventilator-induced lung injury.

269. A method for treating heart failure in a patient requiring treatment for heart failure, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 196, or a composition according to claim 197.

270. The method according to claim 269, wherein the heart failure is heart failure characterized by a reduced ejection fraction.

271. The method according to claim 269, wherein the heart failure is heart failure in which the ejection fraction is preserved.

272. A compound selected from Table 1, or a pharmaceutically acceptable salt or deuterated form thereof.

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